A retrospective study evaluating the impact of scattering radiation from imaging procedures on oocyte quality during ovarian stimulation for fertility preservation in young breast cancer patients

Purpose: Ovarian stimulation for oocyte and embryo cryopreservation is the standard of care for fertility preservation in young breast cancer patients before gonadotoxic chemotherapy. The procedure should be started as soon as possible to avoid delay of treatment; thus, it is often performed concomitantly with tumor staging assessments. However, questions remain regarding the potential negative impact on oocyte quality that may occur due to exposure to scattered ionizing radiation from imaging techniques when staging assessment is conducted at the same time as ovarian stimulation. Methods: We conducted a retrospective study on all breast cancer patients who performed ovarian stimulation for fertility preservation at our center between November 2012 and May 2020. Results: Gynecologic and oncological characteristics were similar between patients exposed (n = 14) or not (n = 60) to ionizing radiation. Exposed patients started the ovarian stimulation sooner after diagnosis than non-exposed patients (11.5 vs 28 days, respectively, P < 0.01). Cycle parameters, including the median number of oocytes collected (10.5 vs 7, P = 0.16), maturation rates (92.5% vs 85.7%, P = 0.54), and fertilization rates (62.2% vs 65.4%, P = 0.70), were similar between groups. Conclusion: This study shows that scattered ionizing radiation due to staging assessment appears to be safe without compromising follicular growth and maturation. Larger studies on fertility and obstetrical outcomes are needed to confirm these preliminary data

Reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients

Background: Preclinical evidence suggests a possible negative impact of deleterious BRCA mutations on female fertility. However, limited and rather conflicting clinical data are available. This study assessed the reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients. Patients and methods: This was a retrospective analysis of two prospective studies investigating oocyte cryopreservation and ovarian tissue cryopreservation in newly diagnosed early breast cancer patients. In the current analysis, baseline anti-Mullerian hormone (AMH) and performance of cryopreservation strategies were compared between patients with or without germline deleterious BRCA mutations. Results: Out of 156 patients included, 101 had known BRCA status of whom 29 (18.6%) were BRCA-mutated and 72 (46.1%) had no mutation. Median age in the entire cohort was 31 years [interquartile range (IQR) 28-33). Median AMH levels were 1.8 lg/l (IQR 1.0-2.7) and 2.6 \u3bcg/l (IQR 1.5-4.1) in the BRCA-positive and BRCA-negative cohorts, respectively (P=0.109). Among patients who underwent oocyte cryopreservation (N=29), women in the BRCA-positive cohort tended to retrieve (6.5 versus 9; P=0.145) and to cryopreserve (3.5 versus 6; P=0.121) less oocytes than those in the BRCA-negative cohort. Poor response rate (i.e. retrieval of 644 oocytes) was 40.0% and 11.1% in the BRCA-positive and BRCA-negative cohorts, respectively (P=0.147). Among patients who underwent ovarian tissue cryopreservation (N=72), women in the BRCA-positive cohort tended to have a numerically lower number of oocytes per fragment (0.08 versus 0.14; P=0.193) and per square millimeter (0.33 versus 0.78; P=0.153) than those in the BRCA-negative cohort. Two BRCA-mutated patients were transplanted after chemotherapy and one delivered at term a healthy baby. No difference between BRCA1- and BRCA2-mutated patients was observed in any of the above-mentioned outcomes. Conclusion: A consistent trend for reduced reproductive potential and performance of cryopreservation strategies was observed in BRCA-mutated breast cancer patients. Independent validation of these results is needed

Safety of fertility preservation techniques before and after anticancer treatments in young women with breast cancer: a systematic review and meta-analysis

Study question: Is it safe to perform controlled ovarian stimulation (COS) for fertility preservation before starting anticancer therapies or ART after treatments in young breast cancer patients? Summary answer: Performing COS before, or ART following anticancer treatment in young women with breast cancer does not seem to be associated with detrimental prognostic effect in terms of breast cancer recurrence, mortality or event-free survival (EFS). What is known already: COS for oocyte/embryo cryopreservation before starting chemotherapy is standard of care for young women with breast cancer wishing to preserve fertility. However, some oncologists remain concerned on the safety of COS, particularly in patients with hormone-sensitive tumors, even when associated with aromatase inhibitors. Moreover, limited evidence exists on the safety of ART in breast cancer survivors for achieving pregnancy after the completion of anticancer treatments. Study design, size, duration: The present systematic review and meta-analysis was carried out by three blinded investigators using the keywords 'breast cancer' and 'fertility preservation'; keywords were combined with Boolean operators. Eligible studies were identified by a systematic literature search of Medline, Web of Science, Embase and Cochrane library with no language or date restriction up to 30 June 2021. Participants/materials, setting, methods: To be included in this meta-analysis, eligible studies had to be case-control or cohort studies comparing survival outcomes of women who underwent COS or ART before or after breast cancer treatments compared to breast cancer patients not exposed to these strategies. Survival outcomes of interest were cancer recurrence rate, relapse rate, overall survival and number of deaths. Adjusted relative risk (RR) and hazard ratio (HR) with 95% CI were extracted. When the number of events for each group were available but the above measures were not reported, HRs were estimated using the Watkins and Bennett method. We excluded case reports or case series with <10 patients and studies without a control group of breast cancer patients who did not pursue COS or ART. Quality of data and risk of bias were assessed using the Newcastle-Ottawa Assessment Scale. Main results and the role of chance: A total of 1835 records were retrieved. After excluding ineligible publications, 15 studies were finally included in the present meta-analysis (n = 4643). Among them, 11 reported the outcomes of breast cancer patients who underwent COS for fertility preservation before starting chemotherapy, and 4 the safety of ART following anticancer treatment completion. Compared to women who did not receive fertility preservation at diagnosis (n = 2386), those who underwent COS (n = 1594) had reduced risk of recurrence (RR 0.58, 95% CI 0.46-0.73) and mortality (RR 0.54, 95% CI 0.38-0.76). No detrimental effect of COS on EFS was observed (HR 0.76, 95% CI 0.55-1.06). A similar trend of better outcomes in terms of EFS was observed in women with hormone-receptor-positive disease who underwent COS (HR 0.36, 95% CI 0.20-0.65). A reduced risk of recurrence was also observed in patients undergoing COS before neoadjuvant chemotherapy (RR 0.22, 95% CI 0.06-0.80). Compared to women not exposed to ART following completion of anticancer treatments (n = 540), those exposed to ART (n = 123) showed a tendency for better outcomes in terms of recurrence ratio (RR 0.34, 95% CI 0.17-0.70) and EFS (HR 0.43, 95% CI 0.17-1.11). Limitations, reasons for caution: This meta-analysis is based on abstracted data and most of the studies included are retrospective cohort studies. Not all studies had matching criteria between the study population and the controls, and these criteria often differed between the studies. Moreover, rate of recurrence is reported as a punctual event and it is not possible to establish when recurrences occurred and whether follow-up, which was shorter than 5 years in some of the included studies, is adequate to capture late recurrences. Wider implications of the findings: Our results demonstrate that performing COS at diagnosis or ART following treatment completion does not seem to be associated with detrimental prognostic effect in young women with breast cancer, including among patients with hormone receptor-positive disease and those receiving neoadjuvant chemotherapy. Study funding/competing interest(s): Partially supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC; grant number MFAG 2020 ID 24698) and the Italian Ministry of Health-5 7 1000 funds 2017 (no grant number). M.L. acted as consultant for Roche, Pfizer, Novartis, Lilly, AstraZeneca, MSD, Exact Sciences, Gilead, Seagen and received speaker honoraria from Roche, Pfizer, Novartis, Lilly, Ipsen, Takeda, Libbs, Knight, Sandoz outside the submitted work. F.S. acted as consultant for Novartis, MSD, Sun Pharma, Philogen and Pierre Fabre and received speaker honoraria from Roche, Novartis, BMS, MSD, Merck, Sun Pharma, Sanofi and Pierre Fabre outside the submitted work. I.D. has acted as a consultant for Roche, has received research grants from Roche and Ferring, has received reagents for academic clinical trial from Roche diagnostics, speaker's fees from Novartis, and support for congresses from Theramex and Ferring outside the submitted work. L.D.M. reported honoraria from Roche, Novartis, Eli Lilly, MSD, Pfizer, Ipsen, Novartis and had an advisory role for Roche, Eli Lilly, Novartis, MSD, Genomic Health, Pierre Fabre, Daiichi Sankyo, Seagen, AstraZeneca, Eisai outside the submitted work. The other authors declare no conflict of interest. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript and decision to submit the manuscript for publication. Registration number: N/A

Near-infrared fluorescent probe traces bisphosphonate delivery and retention in vivo

Bisphosphonate use has expanded beyond traditional applications to include treatment of a variety of low-bone-mass conditions. Complications associated with long-term bisphosphonate treatment have been noted, generating a critical need for information describing the local bisphosphonate-cell interactions responsible for these observations. This study demonstrates that a fluorescent bisphosphonate analogue, far-red fluorescent pamidronate (FRFP), is an accurate biomarker of bisphosphonate deposition and retention in vivo and can be used to monitor site-specific local drug concentration. In vitro, FRFP is competitively inhibited from the surface of homogenized rat cortical bone by traditional bisphosphonates. In vivo, FRFP delivery to the skeleton is rapid, with fluorescence linearly correlated with bone surface area. Limb fluorescence increases linearly with injected dose of FRFP; injected FRFP does not interfere with binding of standard bisphosphonates at the doses used in this study. Long-term FRFP retention studies demonstrated that FRFP fluorescence decreases in conditions of normal bone turnover, whereas fluorescence was retained in conditions of reduced bone turnover, demonstrating preservation of local FRFP concentration. In the mandible, FRFP localized to the alveolar bone and bone surrounding the periodontal ligament and molar roots, consistent with findings of osteonecrosis of the jaw. These findings support a role for FRFP as an effective in vivo marker for bisphosphonate site-specific deposition, turnover, and long-term retention in the skeleton. © 2010 American Society for Bone and Mineral ResearchPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77952/1/66_ftp.pd

EFFICIENCY AND SAFETY OF FERTILITY PRESERVATION AND PREGNANCIES IN YOUNG BREAST CANCER PATIENTS

Résumé: Lorsqu’une femme en âge de reproduction est diagnostiquée avec un cancer du sein, le traitement comprend entre autres de la chimiothérapie et/ou une hormonothérapie. Malheureusement, certaines patientes deviendront infertiles suite à la chimiothérapie qui est gonadotoxique, ce qui diminue leurs chances de devenir mères avec leurs propres gamètes. Etant donné que la grossesse après un cancer du sein n’est plus considérée comme un facteur de risque de récidive de la maladie, l’accès à la maternité chez ces jeunes patientes est devenu un enjeu majeur. Cependant, peu de données ont été publiées concernant la sécurité de concevoir grâce à la PMA chez une patiente devenue infertile suite au traitement du cancer du sein.Il est donc primordial d’offrir aux femmes qui le désirent une méthode de préservation de la fertilité avant tout traitement gonadotoxique.La conservation d’ovocytes ou d’embryons après hyperstimulation ovarienne est une des techniques offertes aux patientes. Néanmoins, en cas de maladie hormono- sensible tel que le cancer du sein, une élévation d’hormones stéroïdiennes accompagnant la réponse ovarienne est peu souhaitable. Des protocoles modifiés ont donc été développés, tel que l’hyperstimulation ovarienne aux gonadotrophines associée au letrozole, un inhibiteur de l’aromatase.Malgré certains résultats rassurants dans la littérature, les données concernant l’efficacité et la sécurité de ce protocole sont toutefois limitées.Notre projet comporte 2 objectifs:1. Evaluation d’une procédure de préservation de la fertilité associant une hyperstimulation ovarienne au letrozole (Let-COH), dans une étude prospective non randomisée (BROVALE).2. Evaluation de la sécurité de la grossesse associée à la PMA chez des patientes ayant été traitées pour un cancer du sein.Dans la première partie nous avons confirmé l’efficacité du Let-COH sur base du taux de maturation ovocytaire similaire à une population contrôle de patientes7infertiles ayant bénéficié d’une hyperstimulation ovarienne conventionnelle sans letrozole (groupe contrôle) quel que soient les modes de déclenchement de la maturation ovocytaires utilisés, human chorionic gonadotropin (hCG) ou l’agoniste de la gonadotropin-releasing hormone (GnRHa). Par ailleurs, les modifications endocriniennes dans le liquide folliculaire, et l’expression de gènes liés à la qualité ovocytaire au niveau des cellules du cumulus oophorus (CC) ont été analysées. Dans le microenvironnement entourant l’ovocyte, nous avons observé un taux d’œstradiol significativement plus bas et un taux de testostérone significativement plus élevé dans le groupe Let-COH, comparé au groupe contrôle. Par ailleurs, l’expression génique au niveau des CC était plus basse dans le groupe Let-COH déclenché à l’hCG comparé au groupe contrôle. Cependant l’inverse était observé lorsque le GnRHa était utilisé comme déclencheur de l’ovulation. Ces résultats suggèrent donc un effet bénéfique des analogues de la GnRH sur la qualité ovocytaire avec le Let-COH.Nous avons montré que le taux d’oestradiol était bas durant la stimulation, mais que le taux de progestérone durant la phase lutéale était supra-physiologique chez les patientes ayant reçu le Let-COH, comparable au taux des patientes contrôles.Etant donné le rôle potentiel de la progestérone dans la carcinogenèse mammaire, nous avons modifié le protocole de déclenchement de l’ovulation, pour administrer le GnRHa au lieu de l’hCG.Dans la seconde partie de notre travail, nous avons réalisé une étude rétrospective multicentrique afin de comparer les issues oncologiques et de grossesse de patientes ayant été enceintes après cancer du sein, naturellement (n=173) ou grâce à la PMA (n=25). Malgré la petite taille de l’échantillon obtenu, nous n’avons pas observé plus de récidives chez les patientes ayant eu recours à la PMA.En conclusion, ce projet nous a permis de démontrer l’efficacité de la préservation de la fertilité chez les jeunes patientes atteintes de cancer du sein, par hyperstimulation associée au letrozole. Nous avons également observé que le risque de récidive de la maladie n’était pas majoré dans notre échantillon limité de patientes enceintes suite à la PMA après cancer du sein.Abstract:Young women diagnosed with breast cancer are often treated with adjuvant primary therapy, including chemo and/or endocrine therapy. These women may face infertility or premature ovarian failure due to the gonadotoxicity of chemotherapy regimens or to aging, which significantly decreases their chances to become mothers with their own gametes. Since it has been established that pregnancy after breast cancer does not increase the risk of relapse, assisting young breast cancer survivors to access motherhood has become a major quality of life issue. However, data on the safety of pregnancies associated with ART in patients who became infertile are scarce. Therefore, it is recommended that young patients diagnosed with breast cancer be informed about treatment-related infertility risks and available procedures to preserve their fertility before undergoing gonadotoxic treatment.Oocyte and/or embryo cryopreservation following controlled ovarian hyperstimulation (COH) is the most established fertility preservation procedure that patients can undergo before initiation of chemotherapy. However, this procedure induces an increase in steroid levels, which may be detrimental in hormonally sensitive diseases such as breast cancer. In order to avoid this issue, a modified protocol has been developed a decade ago, combining letrozole (an aromatase inhibitor) with conventional COH (Let-COH).Despite recent reassuring preliminary results reported in the literature, data are still very limited regarding the efficiency and the safety of this protocol.Thus, the aims of this project were:1. Evaluation of the efficiency of Let-COH before adjuvant therapy, in anonrandomized prospective study (BROVALE).2. Evaluation of the safety of ART-associated pregnancy in breast cancersurvivors.In the first part, we confirmed the efficiency of Let-COH (study group) based on similar oocyte maturation rates when compared to infertile patients undergoing conventional COH without letrozole (control group), regardless of the triggering5method, human chorionic gonadotropin (hCG) or GnRH-agonist (GnRHa). Oocyte quality was indirectly assessed by analysis of follicular fluid (FF) steroid levels and cumulus cell (CC) gene expression (HAS2, PTGS2, and GREM1). We found that estradiol levels were significantly lower and testosterone levels significantly higher in the study compared to the control group, suggesting lower oocyte quality. Nevertheless, when GnRHa was used as ovulation trigger, differences in estradiol levels between the groups were reduced. Similarly, CC gene expression was lower in the study group compared to the control group in the hCG triggered subpopulation, while the opposite effect was observed in the GnRH-agonist triggered subpopulation. Altogether, the results suggest a benefit of GnRHa trigger on oocyte quality in Let- COH protocol.The safety of the protocol was assessed by measuring estradiol and progesterone levels during and after Let-COH. We confirmed that estradiol levels remained low during treatment. However, during luteal phase, progesterone levels were comparable to conventional COH when triggered with hCG, but not with GnRHa. Since progesterone may be as important as estradiol in promoting breast carcinogenesis, we modified the protocol to systematically use GnRH-agonist as ovulation trigger.In the second part of our project, we conducted a retrospective multicenter study to compare pregnancy and oncological outcomes among breast cancer survivors who subsequently conceived spontaneously (n=173) or following ART (n=25). Although the ART group’s sample size was small, we did not observe an increased relapse rate after ART compared to patients who conceived naturally.In conclusion, we confirmed the feasibility and efficiency of Let-COH as a method of fertility preservation in breast cancer patients. Moreover, in our small series of ART- associated pregnancies in breast cancer survivors we did not observe an increased risk of disease recurrence.Doctorat en Sciences médicales (Médecine)info:eu-repo/semantics/nonPublishe

Agénésies des incisives latérales maxillaires permanentes (de la génétique à l'orthodontie)

MONTROUGE-BUFR Odontol.PARIS5 (920492101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Pathologies génétiques des collagènes et conséquences sur le développement cranio-facial

La matrice extra-cellulaire donne aux tissus leurs propriétés mécaniques et aux cellules, un réservoir de signaux locaux ou régionaux régulant leur fonctionnement. Présentant des similitudes, les collagènes des matrices osseuses et cartilagineuses sont cependant codés par des gènes différents. Par l'étude d'une pathologie génétique du collagène I majoritaire dans l'os, l'ostéogenèse imparfaite, et sa comparaison avec des pathologies du collagène cartilagineux (syndromes de Stickler et de Kniest), nous tenterons d'éclairer le rôle de ces molécules dans les phénotypes cranio-faciaux rencontrés

Ostéogenèse imparfaite et dentinogenèse imparfaite : frontières diagnostiques et intérêt en orthopédie dento-faciale

L'ostéogenèse imparfaite est une maladie génétique de sévérité variable et caractérisée par une augmentation de la fragilité osseuse responsable de nombreuses fractures. Des manifestations extra-squelettiques peuvent être observées : sclérotiques bleues, dentinogenèse imparfaite, surdité. Dans la plupart des cas, une anomalie du collagène I est responsable de la maladie. Cette pathologie s'accompagne d'une morphologie cranio-faciale particulière, avec une typologie de classe III, des béances, et une prévalence augmentée d'inclusion des molaires permanentes. L'orthodontiste confronté à de tels patients devra prendre en compte l'état dentaire, observer les précautions antibactériennes et antihémorragiques, et connaître les effets secondaires des bisphosphonates, traitement médical actuel

Impact of letrozole-associated controlled ovarian hyperstimulation on ART outcomes and endocrinological parameters.

info:eu-repo/semantics/publishe