Vincent Lavoué

Aminobisphosphonate-pretreated dendritic cells trigger successful Vγ9Vδ2 T cell amplification for immunotherapy in advanced cancer patients

Hepatocellular carcinoma (HCC) and colorectal carcinoma with hepatic metastases (mCRC) are cancers with poor prognosis and limited therapeutic options. New approaches are needed and adoptive immunotherapy with Vγ9Vδ2 T lymphocytes represents an attractive strategy. Indeed, Vγ9Vδ2 T cells were shown to exhibit efficient lytic activity against various human tumor cell lines, and in vitro Vγ9Vδ2 T expansion protocol based on single phosphoantigen stimulation could be easily performed for healthy donors. However, a low proliferative response of Vγ9Vδ2 T cells was observed in about half of the cancer patients, leading to an important limitation in the development of Vγ9Vδ2 T cell-based immunotherapy. Here, for the first time in the context of cancer patients, Vγ9Vδ2 T cell expansions were performed by co-culturing peripheral blood mononuclear cell (PBMCs) with autologous dendritic cells (DCs) pretreated with aminobisphosphonate zoledronate. For patients not responding to the conventional culture protocol, co-culture of PBMC with zoledronate-pretreated DCs induced strong cell expansion and allowed reaching a minimal rate of purity of 70% of Vγ9Vδ2 T cells. The potent immunostimulatory activity of zoledronate-treated DCs was associated with higher amount of isopentenyl pyrophosphate (IPP) in the culture and was correlated with better ability to activate Vγ9Vδ2 T cells as measured by IFN-γ production. Moreover, we demonstrated that the cytotoxic level of Vγ9Vδ2 T cells against freshly autologous tumor cells isolated from patients could be significantly increased by pretreating the tumor cells with zoledronate. Thus, this method of generating Vγ9Vδ2 T cells leads eligible for Vγ9Vδ2 T cell adoptive immunotherapy the HCC and mCRC patients.

Pregnancy loss: French clinical practice guidelines

In intrauterine pregnancies of uncertain viability with a gestational sac without a yolk sac (with a mean of three orthogonal transvaginal ultrasound measurements <25mm), the suspected pregnancy loss should only be confirmed after a follow-up scan at least 14 days later shows no embryo with cardiac activity (Grade C). In intrauterine pregnancies of uncertain viability with an embryo <7mm on transvaginal ultrasound, the suspected pregnancy loss should only be confirmed after a follow-up scan at least 7 days later (Grade C). In pregnancies of unknown location after transvaginal ultrasound (i.e. not visible in the uterus), a threshold of at least 3510IU/l for the serum human chorionic gonadotrophin assay is recommended; above that level, a viable intrauterine pregnancy can be ruled out (Grade C). Postponing conception after an early miscarriage in women who want a new pregnancy is not recommended (Grade A). A work-up for women with recurrent pregnancy loss should include the following: diabetes (Grade A), antiphospholipid syndrome (Grade A), hypothyroidism with anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies (Grade A), vitamin deficiencies (B9, B12) (Grade C), hyperhomocysteinaemia (Grade C), hyperprolactinaemia (Grade B), diminished ovarian reserve (Grade C), and a uterine malformation or an acquired uterine abnormality amenable to surgical treatment (Grade C). The treatment options recommended for women with a missed early miscarriage are vacuum aspiration (Grade A) or misoprostol (Grade B); and the treatment options recommended for women with an incomplete early miscarriage are vacuum aspiration (Grade A) or expectant management (Grade A). In the absence of both chorioamnionitis and rupture of the membranes, women with a threatened late miscarriage and an open cervix, with or without protrusion of the amniotic sac into the vagina, should receive McDonald cerclage, tocolysis with indomethacin, and antibiotics (Grade C). Among women with a threatened late miscarriage and an isolated undilated shortened cervix (<25mm on ultrasound), cerclage is only indicated for those with a history of either late miscarriage or preterm delivery (Grade A). Among women with a threatened late miscarriage, an isolated undilated shortened cervix (<25mm on ultrasound) and no uterine contractions, daily treatment with vaginal progesterone up to 34 weeks of gestation is recommended (Grade A). Hysteroscopic section of the septum is recommended for women with a uterine septum and a history of late miscarriage (Grade C). Correction of acquired abnormalities of the uterine cavity (e.g. polyps, myomas, synechiae) is recommended after three early or late miscarriages (Grade C). Prophylactic cerclage is recommended for women with a history of three late miscarriages or preterm deliveries (Grade B). Low-dose aspirin and low-molecular-weight heparin at a preventive dose are recommended for women with obstetric antiphospholipid syndrome (Grade A). Glycaemic levels should be controlled before conception in women with diabetes (Grade A).

Restoration of ovulation after unilateral ovariectomy in a woman with McCune-Albright syndrome : a case report

INTRODUCTION McCune-Albright syndrome (MAS) is characterized by peripheral precocious puberty, café-au-lait spots, and polyostotic fibrous dysplasia. This syndrome is due to a post-zygotic mutation of the GNAS1 gene with mosaic distribution and unilateral predominance. Clinical manifestations depend on the tissues carrying the mutation. We describe the ovarian function before and after unilateral ovariectomy in a woman with MAS and bilateral distribution of the GNAS1 gene mutation. CASE REPORT A 33-year-old patient, previously diagnosed as having MAS, presented irregular menstrual cycles (30-180 days) and monophasic temperature curves. Transvaginal ultrasound and blood tests were repeated at 3-day intervals over 3 months. Findings included a persistent quiescent left ovary, a persistent polycystic right ovary, constantly high estradiol-17beta (E2) levels, and very low FSH and LH levels. She also presented severe persistent pelvic pain. Because of unilateral ovarian activity, a unilateral right ovariectomy was performed as well as biopsy of the remaining left ovary. A GNAS1 gene mutation was identified in both ovaries. A regular monthly menstrual cycle was immediately restored. On day 3 of the menstrual cycle, E2 level was 30 pg/ml, FSH level was 7.5 mIU/ml, and LH level was 6.4 mIU/ml. On day 17, pelvic ultrasound showed one follicle of 25 mm in the left ovary. On day 21, the progesterone level was 13.1 ng/ml. DISCUSSION This is the first report of ovulation being restored following unilateral ovariectomy in an adult patient suffering from severe MAS with GNAS1 gene mutation identified in both ovaries.

Uterus transplantation in France: for which patients?

OBJECTIVE Uterine infertility (UI), which can be caused by a variety of congenital or acquired factors, affects several thousand women in Europe. Uterus transplantation (UTx), at the current stage of research, offers hope for these women to be both the biological mother and the carrier of their child. However, the indications of UTx still need to be defined. The main aim of the study was to describe the different etiologies of UI and other data as marital and parental status from women requesting UTx who contacted us in the framework of a UTx clinical trial. Secondarily, we discussed the potential indications of UTx and their feasibility. STUDY DESIGN This is an observational study. RESULTS Of a total of 139 patients with UI, 105 patients (75.5%) had uterine agenesis, making it the leading cause of UI in this sample. Among the patients with uterine agenesis, 25% had a solitary kidney and 44.7% had undergone vaginal reconstruction. Peripartum hysterectomy, hysterectomy for cancer, and hysterectomy for benign pathologies accounted for 9.4%, 7.2% and 5% of cases, respectively. Less common causes of UI included complete androgen insensitivity syndrome (2.2% of patients) and prenatal diethylstilbestrol exposure (0.7%). Approximately 14% of the women already had at least one child and 66% were in a couple living together for at least 2 years. CONCLUSION UTx is still under evaluation and further research is under way. Nulliparous patients with no major medical or surgical history and with normal ovarian function, who meet the legal criteria for medically assisted reproduction, represent the best indications for UTx at this stage of its development.

Patterns of recurrence and outcomes in surgically treated women with endometrial cancer according to ESMO-ESGO-ESTRO Consensus Conference risk groups: Results from the FRANCOGYN study Group

OBJECTIVES The purpose of this study was to analyse the endometrial cancer (EC) patterns of recurrence based on a large French multicentre database according to ESMO-ESGO-ESTRO classification. METHODS Data of women with histologically proven EC who received primary surgical treatment between January 2001 and December 2012 were retrospectively abstracted from seven institutions with prospectively maintained databases. The endpoints were recurrence, recurrence free survival (RFS) and overall survival (OS). Time to the first EC recurrence in a specific site was evaluated by using cumulative incidence analysis (Grays test). RESULTS Data from 829 women were analysed in whom recurrences were observed in 176 (21%) with a median and mean time to recurrence of 13 and 19.5months, respectively. High (35%) and high-intermediate risk groups (16%) were associated with higher recurrence rates compared with low (9%) and intermediate (9%) risk patients (p<0.0001). Women with high risk EC had a higher 5-year cumulative incidence of distant recurrence (20.7%) than women with high-intermediate, intermediate and low risk EC (5.6%, 3.5%, 3.3%), (p<0.001), respectively. Women with high risk and high-intermediate risk EC had a higher 5-year cumulative incidence of loco-regional recurrence (24.3% and 16.6%, respectively) than women with intermediate and low risk EC (6.6% and 6.5%, respectively), (p<0.001). CONCLUSIONS We report specific time and site patterns of first recurrence according to the ESMO/ESGO/ESTRO classification. Sites and hazard rates for recurrence differ widely between subgroups over time. Defining patterns of EC recurrence may provide useful information for developing follow-up recommendations and designing therapeutic approaches.

Recommandations françaises pour les critères diagnostiques d’arrêt de grossesse au premier trimestre et stratégie de prise en charge des patientes présentant une menace de fausse couche ou une grossesse arrêtée (hors évacuation utérine)

OBJECTIVE To assess value of sonography, hCG and progesterone for diagnosis of first trimester nonviable pregnancy and to assess first trimester miscarriage management (except evacuation). METHODS French and English publications were searched using PubMed, Cochrane Library and international learned societies recommendations. RESULTS First trimester nonviable pregnancy is established with gestational sac mean diameter and embryo crown-rump length. Mean sac diameter≥25mm without embryo (LE2) or embryo crown-rump length≥7mm without heartbeat (LE2) by transvaginal sonography allows to diagnose pregnancy failure. Intrauterine pregnancy of uncertain viability is defined by intra-uterine gestational sac without embryo with heartbeat or without pregnancy diagnosis failure and requires a new transvaginal sonography. The delay for this second sonography depends on the aspect of intrauterine picture (i.e. presence of yolk sac or not, presence of embryo or not) (LE4). Human chorionic gonadotropin (hCG) and progesterone are useful for pregnancy of unknown location (i.e. no gestational sac at transvaginal sonography): hCG ratio<15% between two-day serum samples when first hCG is<2000UI/mL (LE2) or low serum progesterone level (<3.2ng/mL) (LE2) exclude viable intrauterine pregnancy. There is not known prevention strategy for threatened miscarriage.

Fertility, Pregnancy, and Clinical Outcomes after Uterine Arteriovenous Malformation Management

STUDY OBJECTIVE To evaluate fertility, pregnancy, and clinical outcomes after uterine arteriovenous malformation (UAVM) management. DESIGN Single-center retrospective study (Canadian Task Force classification III). SETTING One referral center. PATIENTS Twenty-two patients with a UAVM diagnosed by magnetic resonance angiography or computed tomography angiography and managed by expectant management (EM) or uterine arterial embolization (UAE) during the study period were included. INTERVENTIONS Nine of 22 patients underwent first-intention EM and 13 first-line UAE. Three of 9 EM patients (33.3%) required emergency second-intention UAE for nonresolution of the UAVM and severe genital bleeding. MEASUREMENTS AND MAIN RESULTS To analyze fertility according to management approach, we defined 2 groups: EM only group (n = 6) and UAE group (n = 16; women who underwent first- or second-intention UAE). Overall, the median age was 29 years (range, 17-43). The mean follow-up after UAVM management was 39 months (range, 1-116). The success rate of the UAE procedure was 87.5% (14/16). Eight of 12 women (66.7%) who wished to conceive became pregnant: 2 of 5 (33.3%) in the EM group and 6 of 7 (85.7%) in the UAE group (p = 1). Overall, 11 patients (50%) conceived: 3 in the EM group (50%) and 8 in the UAE group (50%) (p = .9). The live birth rate was 36.4% (8/22) for the whole population. There were no miscarriages or ectopic pregnancies. The 8 women (72.7%) wishing to conceive who became pregnant all delivered: 1 by cesarean section and 7 by vaginal delivery. Median duration of pregnancy was 39 weeks and 5 days. The remaining 3 women (i.e., women who conceived but did not wish to become pregnant) had therapeutic abortions. One complication was experienced in the EM group (small for gestational age newborn) and none in the UAE group (p = .3). Limitations include retrospective design and small sample size. CONCLUSION UAE for UAVM is an effective and safe technique. It does not impair fertility, and obstetric prognosis is good.

A prospective study of the frequency of severe pain and predictive factors in women undergoing first-trimester surgical abortion under local anaesthesia

OBJECTIVE To determine the frequency of severe pain among women and to identify the associated predictive factors during first-trimester surgical abortion under local anaesthesia (LA). STUDY DESIGN A prospective cohort study from November 2013 to January 2014 at the Department of Gynecology and Obstetrics, Rennes, France. The study population was composed of one hundred and ninety-four patients who underwent an elective first-trimester surgical abortion under LA. In an anonymized questionnaire, the participants were asked to self-record their perceived pain level 30 min after the completion of the procedure using a 10 cm visual analogue scale (VAS). The main outcome measure was the frequency of severe pain among women, defined as VAS ≥ 7. Secondary outcome measure was the risk factor(s) for severe pain. RESULTS Severe pain (i.e. VAS ≥ 7) was experienced by 46% (95% CI: 39%-53%) of the population. Multivariate analysis confirmed that >10 weeks of gestation (OR: 2.530 [95% CI: 1.1-5.81], p = .0287) and having 0 or 1 child (OR: 5.206 [95% CI: 1.87-14.49], p = .0016) were significant independent factors of severe pain. CONCLUSION Nearly half of the women experienced severe pain. More than 10 weeks of gestation and parity were predictive factors of severe pain. These findings should be useful in counselling women undergoing surgical abortion under LA.

Serial hCG and progesterone levels to predict early pregnancy outcomes in pregnancies of uncertain viability: A prospective study

OBJECTIVE To assess the value of serial hCG and progesterone serum level in the diagnosis of early pregnancy viability. METHODS It was a prospective cohort study. Women with a pregnancy of uncertain viability (PUV), defined as the presence of an intra-uterine embryo with a crown-rump length <7mm with no cardiac activity or an intra-uterine gestational sac size <25mm with no visible embryonic structure in a transvaginal ultrasound scan (TVS) were eligible. The diagnosis value of serial plasmatic hCG levels on the first day and 48h after as well as the initial progesterone level were evaluated to diagnose pregnancy viability. Pregnancy viability was assessed by TVS 7 to 14days after inclusion. RESULTS The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of an hCG H48/H0 ratio increase <11% to diagnose an early pregnancy loss were 70.6%, 100%, 100% and 85.3%, respectively. The sensitivity, specificity, PPV and NPV of a 6.2ng/ml progesterone level to diagnose an early pregnancy loss were 20%, 100%, 100% and 65.2%, respectively. The sensitivity, specificity, PPV and NPV of an hCG H48/H0 ratio increase >75% to diagnose a viable pregnancy were 100%, 31%, 45.9% and 100%, respectively. hCG H48/H0 ratio increase <11% was associated with early pregnancy loss in 100% of the cases. hCG H48/H0 ratio increase >75% was associated with 100% of viable pregnancies in 100% of the cases. CONCLUSION Serial hCG levels alone permitted an early viability diagnosis within 48h for 41.1% of patients with PUV instead of 7 to 14days with TVS.

Ultrasound Presentation of a Disseminated Fetal and Neonatal Rhabdoid Tumor

This is a case report of a disseminated fetal rhabdoid tumor discovered at 32 weeks of gestation in a 29-year-old woman on immunosuppressive therapy. The mother consulted for a decrease in fetal movement. Fetal ultrasound showed signs of a disseminated tumor affecting the left armpit, liver, spleen, and limbs. A caesarian section was performed because of signs of fetal distress. Immunohistochemical analysis of a fetal biopsy showed deletion of the SMARCB1 gene. Pathological analysis of the placenta showed a rhabdoid tumor invading both fetal and maternal compartments. The mother underwent a whole-body MRI, and no metastasis was found. To the best of our knowledge, this is the first report of a disseminated rhabdoid tumor invading both fetal and maternal compartments.