Effect of temozolomide on male gametes: an epigenetic risk to the offspring?

INTRODUCTION: 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. METHODS: 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. RESULTS: Sperm counts decrease significantly and hypomethylation of the H19 locus increase with time even staying in the normal range. CONCLUSION: 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.

[Single-embryo transfer: Rennes' Hospital experience]. / Transfert monoembryonnaire : expérience du CHU de Rennes.

In 2005-2006, 905 punctures of oocytes were realised in the Assisted Reproductive Technology Centre of Rennes' Hospital in France, the source of 173 pregnancies after fresh embryos transfers and 185 pregnancies after frozen embryos transfers. The single-embryo transfer (SET) was proposed in all patients aged less than 38 years with at least two embryos type I or II on the first two cycles. Sixty-three percent of patients (n=293 cycles) chose the SET with 21.5% pregnancies through fresh embryo transfer. The SET with frozen embryos has been completed on 708 cycles with 16.8% of pregnancies per transfer. The cumulative rate of pregnancies by puncture is 39% and the overall risk of multiple pregnancies has dropped to 12%. The SET associated with an effective embryo cryopreservation therefore allows to reduce the risk of multiple births while maintaining a satisfactory pregnancy cumulative rate.

[Pyoderma gangrenosum and breast cancer: a case report]. / Pyoderma gangrenosum et cancer du sein : à propos d'un cas.

The authors report a case of pyoderma gangrenosum (PG) following a breast lumpectomy for a relapse of a breast cancer. The treatment has associated a systemic corticosteroid therapy and local wound care with vacuum assisted closure Vacuum-Assisted Closure and skin graft.

[The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: clinical description and genetics]. / Le syndrome de Mayer-Rokitansky-Küster-Hauser (MRKH) : clinique et génétique.

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by congenital aplasia of the uterus and the upper part (two-third) of the vagina. It may be isolated (type I) or associated with other malformations (type II or MURCS association). These latter involve the upper urinary tract, the skeleton and, to a lesser extent, the otologic sphere or the heart. The incidence of MRKH syndrome has been estimated as 1 in 4500 women. The prime feature is a primary amenorrhea in women presenting otherwise with normal development of secondary sexual characteristics and normal external genitalia. However, the vagina is reduced to a vaginal dimple with variable depth. The ovaries are normal and functional as well as the endocrine status. Karyotype is 46,XX, with no visible chromosome modification. The phenotypic manifestations of MRKH syndrome overlap with various other syndromes or malformations and thus require accurate delineation as well as differential diagnosis. For a long time, the syndrome has been considered as a sporadic anomaly, but increasing familial cases now support the hypothesis of a genetic cause currently under investigation. The syndrome appears to be transmitted as an autosomal dominant trait with incomplete penetrance and variable expressivity.

[Breast cancer prevention: from chemoprevention to prophylactic surgery]. / Prévention des cancers du sein : de la chimioprévention à la chirurgie prophylactique.

INTRODUCTION: The breast cancer prevention is based on mastectomy hormonal deprivation (surgical or chemical) and the use of drugs acting on cell signalization pathways, which provoke the cancerization (these drugs are not officially authorized in France). MATERIAL AND METHODS: Analysis of the literature selected from the Medline base on the keywords: breast cancer; chemoprevention; prophylactic surgery; tamoxifene; raloxifene; BRCA. RESULTS: Four trials on the chemoprevention by tamoxifene show a reduction in the breast cancer incidence from 22% up to 33% in the treated patients, limited to oestrogen-dependant cancers, especially in the populations at risk high (histological or genetic) even in the event of concomitant hormonal replacement therapy. The benefit seems continue in time. Raloxifene and tamoxifene effects are comparable with bone benefits and a less risk of endometrial cancer for raloxifene, but the risk of venous thrombosis is still persisting. The breast prophylactic surgery is effective mainly in case of genetic elevated risk when it is practiced in the young age, and requires a patient agreement (the decision needs to follow the patient advice after complete information). The prophylactic ovariectomy has a positive impact on the mammal risk even in the high genetic risk women. CONCLUSION: The breast cancer prevention requires a better selection of the patients, an adaptation of the type of prevention taking account of the balance risks and benefits (mammals and extramammals) before a clinical use in routine.

[Bladder erosion few years after TVT procedure]. / Erosion vésicale tardive après pose de TVT.

The surgical treatment of the stress urinary incontinence mainly use tension free vaginal tape done through the Retzius space: a case of bladder erosion occurring 5 years after a TVT (Gynecare-Ethicon, USA) procedure is reported. First clinical signs occur 2 years after the operation and the removal of the tape (included in the muscle of the bladder) by vaginal and sus-pubic route was necessary 5 years later because the quality of life was dramatically altered. This complication could be related to the patient (past hysterectomy, history of fibrosis surrounding a mammary implant, Gougerot-Sjögren disease) or to the surgeon with a technical defect during the TVT procedure. The late complications of TVT procedure should be recorded in a national register.

[Uterine cervical lesions during pregnancy: diagnosis and management]. / Lésions cervicales utérines pendant la grossesse: diagnostic et prise en charge.

OBJECTIVES: To define a practical attitude for the management of pregnant women with cervical intraepithelial neoplasia (CIN) and cervical cancer. MATERIALS AND METHODS: Review of the literature indexed in Medline. RESULTS: The prevalence of the HPV infections is unchanged among pregnant women with infection by low risk viruses. The viral load increases at the time of the pregnancy, and decreases in the post-partum period. Cervical cytology is easily to perform with reliable results: among the 5% of pathological cervical smears, low grade lesions predominate. The high grade smears require colposcopic exploration, usefully completed by directed biopsies to rule out invasive lesions. Surveillance of high grade CIN is required during pregnancy with post-partum control; most regress. In France during the year 2000, 189 cancers of the uterine cervix were detected during 774.782 pregnancies. Clinical diagnosis is delayed by the non specific clinical signs and the histological aspects of the lesions which are identical with those observed in young woman. The intrinsic outcome of cancer is not modified by pregnancy, and the cesarean section is often preferred (vaginal delivery likely facilitates vascular dissemination). For fetal reasons, a therapeutic delay can be proposed for small sized lesions with a favourable histological subtype and no progression after 20 weeks of gestation. CONCLUSION: Pregnancy offers the opportunity to perform cervical smears in women not regularly followed. A conservative attitude with a revaluation in postpartum can be proposed in the event of diagnosis of CIN during pregnancy. Pregnancy has little influence on invasive cervical cancers. Management decisions must be made on a case-by-case basis.

[Breast and ovarian cancer due to BRCA1&2 hereditary cancer predisposition syndrome and reproduction: literature review]. / Cancers du sein et de l'ovaire liés aux mutations constitutionnelles délétères BRCA1&2 et reproduction: revue de la littérature.

INTRODUCTION: Germline mutations BRCA1&2 are responsible in women for breast and ovarian cancers that commonly occur at a young age: as such, there are strong interactions between the oncological risks and the events of reproductive life, pregnancy, breastfeeding, and management of infertility. MATERIALS AND METHODS: A review of the international literature from the PubMed database was conducted, and recommendations of French health agencies were exposed. Published studies are case-control and cohort studies in the majority, with a low level of evidence. RESULTS: Pregnancy and lactation have no effect on breast and ovaries or even decreases the risk. The sex ratio among patients carrying the mutation is in favor of girls. It is not observed more infertility in patients carrying a mutation despite a strong suspicion of premature ovarian failure, and infertility treatments do not increase breast and ovarian risk. There are ethical debates concerning the place of pre-natal diagnosis: both experts and concerned patients recommend a case-by-case analysis of the requests.

[Vitrification: Principles and results]. / La vitrification: principes et résultats.

Sperm and embryos cryopreservation is a commonly applied technique for several years. Recently authorized in France, vitrification tends to replace gradually the conventional technique of slow freezing, so upsetting the practices in the management of patients. It allows from now on the cryopreservation of oocytes and opens new perspectives in egg donation either still in fertility preservation. This review thus attempted to examine the contribution of vitrification in the freezing of oocytes and human embryos at various stages of development. If obviously vitrification appears as the current method of choice for the cryopreservation of oocytes as well as blastocysts, the results are less cut as regards embryos to early stages. No increase in adverse obstetric and perinatal outcomes in children conceived from vitrified oocytes or embryos is noted in the literature.

Quality of life and female sexual function after skinning vulvectomy with split-thickness skin graft in women with vulvar intraepithelial neoplasia or vulvar Paget disease.

OBJECTIVE: Vulvar intraepithelial neoplasia (VIN) and vulvar Paget disease are managed with either vulvectomy, destructive treatments (laser, antimitotic drugs) or immunostimulants. All these options are associated with functional complications. The purpose of this study was to evaluate the surgical technique consisting of skinning vulvectomy with split-thickness skin graft, and its effect on overall quality of life and sexual function. METHODS: A retrospective study was conducted on thirteen patients who underwent skinning vulvectomy with split-thickness skin graft between 1999 and 2009. Overall quality of life and sexual function were assessed with the Medical Outcome Study Short Form 36 (MOS SF-36) and Female Sexual Function Index (FSFI), respectively. RESULTS: The median age of patients was 54 (range: 33-77) years. Three patients had Paget disease and 10 patients had VIN lesions. The excision margins were clear in 46% of cases. The incidence of occult cancer was 31%. The mean follow-up period was 77 (±35) months. Four patients experienced a relapse of their intraepithelial disease. The mean disease-free survival was 58 (±44) months. There was no significant difference in MOS SF-36 scores between the study population and the general population. The patients assessed with the FSFI regained normal sexual function after the surgical procedure. CONCLUSION: Skinning vulvectomy with split-thickness skin graft is a feasible technique yielding good results in terms of quality of life and sexual function. It enables occult cancer to be diagnosed in patients with VIN or Paget disease.

[Risk factors and perinatal consequences of short interpregnancy interval: a retrospective case-control study]. / Facteurs de risques et conséquences périnatales des grossesses rapprochées : étude cas-témoin rétrospective.

OBJECTIVES: To study the maternal risk factors and perinatal complications of a short interpregnancy interval. PATIENTS AND METHODS: Retrospective case-control study between 2007 and 2009, comparing a group with a short interpregnancy interval (less than 9 months, n=83), and a control group (interval between two pregnancies between 18 and 24 months, n=166). RESULTS: The main risk factor of short interpregnancy interval is to be unemployed (OR=3.2, P<0.001). There is a significant link between lack of prescription contraceptives in postpartum and a short interval between pregnancies (OR=3.4, P<0.001). We also found a higher rate of anemic women during pregnancy (OR=4.9, P=0.001) and postpartum (OR=2.1, P=0.02) in case of short interpregnancy interval. Short interpregnancy interval increases risk of small for gestational age (OR=2.4, P=0.05) and thermoregulation disorders (OR=3.1, P=0.02). CONCLUSION: A low socioeconomic level is a risk factor of short interpregnancy interval. Short interpregnancy interval is at risk of maternal iron deficiency and neonatal complications like low birth weight and hypothermia.

[Medical abortion from 12 through 14 weeks' gestation: a retrospective study with 126 patients]. / L'interruption volontaire de grossesse médicamenteuse de 12 à 14 semaines d'aménorrhée : étude rétrospective portant sur 126 patientes.

OBJECTIVE: To assess the efficacy of medical abortion performed according to a single protocol from 12 through 14 weeks. STUDY DESIGN: Retrospective observational study of medical abortions from 12 through 14 weeks performed from January 2007 through March 2009. The protocol combined 600 mg de mifepristone orally, followed 48 h later by 400 µg of misoprostol, administered orally, and repeated after 3h, four times a day (during two days), if patient did not begin to abort. Outcome measures were the abortion rate, the rate of complication, the rate of manual uterine revision or vacuum aspiration, the time of expulsion and the misoprostol dose. RESULTS: The study included 126 medical abortions. The abortion rate was 98% and the secondary manual revision or vacuum aspiration rate was 41%. The mean time to expulsion was 10.4 (±8.8)h, and the mean misoprostol dose 1040 (±420) µg. Higher parity was significantly correlated with shorter time to expulsion (P=0.02). CONCLUSION: Medical abortion was consistently effective from 12 through 14 weeks but with high rate of secondary manual revision or vacuum aspiration.

[Acquired uterine arteriovenous malformations]. / Malformations artérioveineuses endo-utérines acquises.

Uterine arteriovenous malformations (AVM) may be responsible for vaginal bleeding potentially life-threatening. They are most often acquired following uterine trauma (curettage, cesarean section, artificial delivery/uterus examination) in association with pregnancy or gestational trophoblastic disease. We report three cases of patients having uterine AVM after curettage. The diagnostic management is important to avoid differential diagnoses (intra-uterine retention, hemangioma, gestational trophoblastic disease). It is based on serum hCG measurement and Doppler ultrasound, then confirmed on dynamic angio-MRI, which tends to replace angiography as first-line. The therapeutic management in cases of symptomatic AVMs is mostly embolization which offers the possibility for childbearing. Current data on subsequent pregnancies is reassuring even if they remain limited.

[Oocyte donation as in France]. / Pour un don d'ovocytes à la française.

Oocyte donation, initially proposed in agonadal women, saw indications expand to ovarian deficiencies and failures of in vitro fertilization (IVF), resulting in a significant increasing demand. The recruitment of oocyte donors is a critical issue for all countries that have allowed this practice. The French legislation, with the laws of bioethics, is clearly the most restrictive of European countries, imposing an absolute free gift from mother. The different solutions in the neighboring countries are analysed and in particular the interpretations made in respect of gratuity and compensation. Motivating donors (spontaneous, relational, or by reciprocity), but also motivating the medical teams can organize a program of oocyte donation in France. The authors present their results of three years experience, demonstrating that this system is possible in the current legislative framework.