Hydroxychloroquine in recurrent pregnancy loss: data from a French prospective multicenter registry.

STUDY QUESTION: What are the outcomes of pregnancies exposed to hydroxychloroquine (HCQ) in women with a history of recurrent pregnancy loss (RPL), and what factors predict the course of these pregnancies beyond the first trimester? SUMMARY ANSWER: In our cohort of pregnancies in women with a history of RPL exposed to HCQ early in pregnancy, we found that the only factor determining the success of these pregnancies was the number of previous miscarriages. WHAT IS KNOWN ALREADY: Dysregulation of the maternal immune system plays a role in RPL. HCQ, with its dual immunomodulating and vascular protective effects, is a potential treatment for unexplained RPL. STUDY DESIGN, SIZE, DURATION: The FALCO (Facteurs de récidive précoce des fausses couches) registry is an ongoing French multicenter infertility registry established in 2017 that includes women (aged from 18 to 49 years) with a history of spontaneous RPL (at least three early miscarriages (≤12 weeks of gestation (WG)) recruited from several university hospitals. PARTICIPANTS/MATERIALS, SETTING, METHODS: Spontaneous pregnancies enrolled in the FALCO registry with an exposure to HCQ (before conception or at the start of pregnancy) were included. Pregnancies concomitantly exposed to tumor necrosis factor inhibitors, interleukin-1 and -2 inhibitors, intravenous immunoglobulin, and/or intravenous intralipid infusion, were excluded. Concomitant treatment with low-dose aspirin (LDA), low-molecular weight heparin (LMWH), progesterone, and/or prednisone was allowed. All patients underwent the recommended evaluations for investigating RPL. Those who became pregnant received obstetric care in accordance with French recommendations and were followed prospectively. The main endpoint was the occurrence of a pregnancy continuing beyond 12 WG, and the secondary endpoint was the occurrence of a live birth. MAIN RESULTS AND THE ROLE OF CHANCE: One hundred pregnancies with HCQ exposure in 74 women were assessed. The mean age of the women was 34.2 years, and the median number of previous miscarriages was 5. Concomitant exposure was reported in 78 (78%) pregnancies for prednisone, 56 (56%) pregnancies for LDA, and 41 (41%) pregnancies for LMWH. Sixty-two (62%) pregnancies ended within 12 WG, the other 38 (38%) continuing beyond 12 WG. The risk of experiencing an additional early spontaneous miscarriage increased with the number of previous miscarriages, but not with age. The distributions of anomalies identified in RPL investigations and of exposure to other drugs were similar between pregnancies lasting ≤12 WG and those continuing beyond 12WG. The incidence of pregnancies progressing beyond 12 WG was not higher among pregnancies with at least one positive autoantibody (Ab) (i.e. antinuclear Ab titer ≥1:160, ≥1 positive conventional and/or non-conventional antiphospholipid Ab, and/or positive results for ≥1 antithyroid Ab) without diminished ovarian reserve (18/51, 35.3%) than among those without such autoantibody (18/45, 40.0%) (P = 0.63). Multivariate analysis showed that having ≤4 prior miscarriages was the only factor significantly predictive for achieving a pregnancy > 12 WG, after adjustment for age and duration of HCQ use prior to conception (adjusted odds ratio (OR) = 3.13 [1.31-7.83], P = 0.01). LIMITATIONS, REASONS FOR CAUTION: Our study has limitations, including the absence of a control group, incomplete data for the diagnostic procedure for RPL in some patients, and the unavailability of results from endometrial biopsies, as well as information about paternal age and behavioral factors. Consequently, not all potential confounding factors could be considered. WIDER IMPLICATIONS OF THE FINDINGS: Exposure to HCQ in early pregnancy for women with a history of RPL does not seem to prevent further miscarriages, suggesting limited impact on mechanisms related to the maternal immune system. STUDY FUNDING/COMPETING INTEREST(S): The research received no specific funding, and the authors declare no competing interests. TRIAL REGISTRATION NUMBER: clinicaltrial.gov NCT05557201.

[First-line management of infertile couple. Guidelines for clinical practice of the French College of Obstetricians and Gynecologists 2022]. / Prise en charge de première intention du couple infertile : mise à jour des RPC 2010 du CNGOF.

OBJECTIVE: To update the 2010 CNGOF clinical practice guidelines for the first-line management of infertile couples. MATERIALS AND METHODS: Five major themes (first-line assessment of the infertile woman, first-line assessment of the infertile man, prevention of exposure to environmental factors, initial management using ovulation induction regimens, first-line reproductive surgery) were identified, enabling 28 questions to be formulated using the Patients, Intervention, Comparison, Outcome (PICO) format. Each question was addressed by a working group that had carried out a systematic review of the literature since 2010, and followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE®) methodology to assess the quality of the scientific data on which the recommendations were based. These recommendations were then validated during a national review by 40 national experts. RESULTS: The fertility work-up is recommended to be prescribed according to the woman's age: after one year of infertility before the age of 35 and after 6months after the age of 35. A couple's initial infertility work-up includes a single 3D ultrasound scan with antral follicle count, assessment of tubal permeability by hysterography or HyFOSy, anti-Mullerian hormone assay prior to assisted reproduction, and vaginal swabbing for vaginosis. If the 3D ultrasound is normal, hysterosonography and diagnostic hysteroscopy are not recommended as first-line procedures. Chlamydia trachomatis serology does not have the necessary performance to predict tubal patency. Post-coital testing is no longer recommended. In men, spermogram, spermocytogram and spermoculture are recommended as first-line tests. If the spermogram is normal, it is not recommended to check the spermogram. If the spermogram is abnormal, an examination by an andrologist, an ultrasound scan of the testicles and hormonal test are recommended. Based on the data in the literature, we are unable to recommend a BMI threshold for women that would contraindicate medical management of infertility. A well-balanced Mediterranean-style diet, physical activity and the cessation of smoking and cannabis are recommended for infertile couples. For fertility concern, it is recommended to limit alcohol consumption to less than 5 glasses a week. If the infertility work-up reveals no abnormalities, ovulation induction is not recommended for normo-ovulatory women. If intrauterine insemination is indicated based on an abnormal infertility work-up, gonadotropin stimulation and ovulation monitoring are recommended to avoid multiple pregnancies. If the infertility work-up reveals no abnormality, laparoscopy is probably recommended before the age of 30 to increase natural pregnancy rates. In the case of hydrosalpinx, surgical management is recommended prior to ART, with either salpingotomy or salpingectomy depending on the tubal score. It is recommended to operate on polyps>10mm, myomas 0, 1, 2 and synechiae prior to ART. The data in the literature do not allow us to systematically recommend asymptomatic uterine septa and isthmoceles as first-line surgery. CONCLUSION: Based on strong agreement between experts, we have been able to formulate updated recommendations in 28 areas concerning the initial management of infertile couples.

Predictors of treatment response to pregabalin in unexplained or refractory chronic cough.

BACKGROUND: Patients with chronic cough (>8 weeks) often remain symptomatic after appropriate investigations and therapeutic trials. Prior research has shown a benefit in certain individuals from pregabalin, but clinical improvement is quite unpredictable and variable. OBJECTIVE: The main objective of this study was to identify the demographic and clinical characteristics associated with a higher likelihood of cough improvement with a trial of pregabalin therapy. METHODS: 50 consecutive patients with chronic cough were enrolled in this prospective cohort study. Subjects were prescribed pregabalin 75 mg oral qhs for 4 weeks followed by 75 mg oral bid. Leicester Cough Questionnaire (LCQ) was completed at treatment initiation and after 3 months of therapy. A comparison was performed between treatment responders (LCQ total score improvement ≥1.3) and non-responders. RESULTS: 56% of patients reported a LCQ total score improvement ≥1.3 (minimal clinically important difference). Responders to pregabalin therapy were more likely to have refractory (with underlying pulmonary disease) versus unexplained chronic cough (p = 0.01). Patients with significant improvement were also on average more symptomatic at baseline (mean LCQ total score 10.2 versus 13.0, p < 0.01). No significant relationship was identified with age, gender, body mass index, history of anxiety and/or depression, cigarette smoking history, or cough duration (p > 0.05). The unexplained chronic cough group had a strong female predominance (85.7% versus 40.9% for refractory cough, p < 0.01). CONCLUSION: This is the first study that has investigated clinical predictors of treatment response to pregabalin in chronic cough patients. Further research is needed to develop therapies for subjects who do not improve with currently available neuromodulating medications.

[Transition, fertility and options for preservation of fertility]. / Transition, fertilité et options de préservation de fertilité.

Oftentimes ignored or infrequently expressed, some transgender persons harbor a desire for parenthood. Given the evolution of medical techniques and the enacting of legislative reforms, it is henceforth possible to propose fertility preservation strategies in the overall context of gender transidentity. During the "female to male" (FtM) transition pathway, androgen therapy has an impact on gonadic function, generally inducing blockage of the ovarian function, with amenorrhea. Even though these events may be reversed on cessation of treatment, the possible long-term effects on future fertility and on the health of children yet to be born are little known. Moreover, transition surgeries definitively compromise the possibility of pregnancy insofar as they involve bilateral adnexectomy and/or hysterectomy. Options for fertility preservation in the framework of FtM transition are premised on cryopreservation of oocytes and/or ovarian tissue. In a comparable manner, even though relevant documentation is lacking, hormonal treatments for persons transitioning from male to female (MtF) can have an impact on future fertility. In the event of surgery involving bilateral orchidectomy in which spermatozoid cryopreservation has not been carried out, fertility is definitively impossible. In both cases and under present-day legislation, numerous legal and regulatory barriers render highly problematic the reutilization of cryopreserved gametes. Given these different constraints, it is indispensable to closely supervise these types of treatment by proposing psychological support.

Secondary infertility with a history of vaginal childbirth: Ready to have another one?

INTRODUCTION: Up to 30% of couples may face secondary infertility. The impact of ectopic pregnancy, spontaneous abortion, pregnancy termination or live birth with caesarean section may impair further fertility in different ways. However, secondary infertility after physiological vaginal life childbirth has been little studied. The aim of this study was to describe the population and the fertility issues and analyze the predictive factors of success in in vitro fertilization in women presenting secondary infertility after a physiological vaginal childbirth. MATERIAL AND METHODS: This single-centre retrospective study included women aged 18-43 years consulting between 2013 and 2020 for secondary infertility in a couple having already had previous vaginal life childbirth. Couples' characteristics, management decision after the first consultation and IVF outcomes were analyzed. RESULTS: Secondary infertility was found in 286 couples, out of whom 138 had a history of vaginal life childbirth. Population was characterized by an advanced female age and overweight. After the first consultation, IVF was performed in only 40% of couples. No predictive factor of live birth was found. CONCLUSION: Our study shows that in couples with secondary infertility after prior physiological delivery cigarette smoking is frequent in male partners, and ovarian reserve markers are altered. However, no statistically significant predictive factor of live birth after IVF treatment has been identified. Further large prospective studies are necessary.

Oocyte Vitrification for Fertility Preservation in Women with Benign Gynecologic Disease: French Clinical Practice Guidelines Developed by a Modified Delphi Consensus Process.

International guidelines are published to provide standardized information and fertility preservation (FP) care for adults and children. The purpose of the study was to conduct a modified Delphi process for generating FP guidelines for BGD. A steering committee identified 42 potential FP practices for BGD. Then 114 key stakeholders were asked to participate in a modified Delphi process via two online survey rounds and a final meeting. Consensus was reached for 28 items. Among them, stakeholders rated age-specific information concerning the risk of diminished ovarian reserve after surgery as important but rejected proposals setting various upper and lower age limits for FP. All women should be informed about the benefit/risk balance of oocyte vitrification-in particular about the likelihood of live birth according to age. FP should not be offered in rASRM stages I and II endometriosis without endometriomas. These guidelines could be useful for gynecologists to identify situations at risk of infertility and to better inform women with BGDs who might need personalized counseling for FP.

The spatiotemporal changes in dopamine, neuromelanin and iron characterizing Parkinson's disease.

In Parkinson's disease, there is a progressive reduction in striatal dopaminergic function, and loss of neuromelanin-containing dopaminergic neurons and increased iron deposition in the substantia nigra. We tested the hypothesis of a relationship between impairment of the dopaminergic system and changes in the iron metabolism. Based on imaging data of patients with prodromal and early clinical Parkinson's disease, we assessed the spatiotemporal ordering of such changes and relationships in the sensorimotor, associative and limbic territories of the nigrostriatal system. Patients with Parkinson's disease (disease duration < 4 years) or idiopathic REM sleep behaviour disorder (a prodromal form of Parkinson's disease) and healthy controls underwent longitudinal examination (baseline and 2-year follow-up). Neuromelanin and iron sensitive MRI and dopamine transporter single-photon emission tomography were performed to assess nigrostriatal levels of neuromelanin, iron, and dopamine. For all three functional territories of the nigrostriatal system, in the clinically most and least affected hemispheres separately, the following was performed: cross-sectional and longitudinal intergroup difference analysis of striatal dopamine and iron, and nigral neuromelanin and iron; in Parkinson's disease patients, exponential fitting analysis to assess the duration of the prodromal phase and the temporal ordering of changes in dopamine, neuromelanin or iron relative to controls; and voxel-wise correlation analysis to investigate concomitant spatial changes in dopamine-iron, dopamine-neuromelanin and neuromelanin-iron in the substantia nigra pars compacta. The temporal ordering of dopaminergic changes followed the known spatial pattern of progression involving first the sensorimotor, then the associative and limbic striatal and nigral regions. Striatal dopaminergic denervation occurred first followed by abnormal iron metabolism and finally neuromelanin changes in the substantia nigra pars compacta, which followed the same spatial and temporal gradient observed in the striatum but shifted in time. In conclusion, dopaminergic striatal dysfunction and cell loss in the substantia nigra pars compacta are interrelated with increased nigral iron content.

Three Decades of Malignant Pleural Mesothelioma: An Academic Center Experience.

BACKGROUND: Malignant pleural mesothelioma (MPM) remains a challenging disease to manage. In the past few decades, extrapleural pneumonectomy (EPP), pemetrexed-based chemotherapy, and indwelling pleural catheters were introduced to MPM care with variable levels of efficacy and evidence. PATIENTS AND METHODS: This was a retrospective review of patients diagnosed with MPM between January 1991 and March 2019. The primary outcome was overall survival (OS). Data were examined by decade to assess trends in MPM demographics, management, and OS. A subgroup analysis was then conducted to examine the impact of EPP, pemetrexed, and indwelling pleural catheters on OS. RESULTS: The study included 337 patients; 309 patients had died at last follow-up (91.7%). Median age at diagnosis and the proportion of female patients increased from 65.8 years (interquartile range [IQR], 57.1-73.7) and 11.6% female from 1991 to 1999 to 75 years (IQR, 68.1-80.6) and 20.5% female from 2010 to 2019. Median OS was largely unchanged in the three study periods: 9.0 months (95% confidence interval [CI], 6.9-12.7) in the 1991-1999 cohort, 9.3 months (95% CI, 7.6-13.2) in the 2000-2009 cohort, and 10.1 months (95% CI, 7.9-13.6) in the 2010-2019 cohort. Controlling for a number of demographic and prognostic factors, EPP (hazard ratio [HR] = 0.50; 95% CI, 0.3-0.9; P = .02), pemetrexed-based chemotherapy (HR = 0.59; 95% CI, 0.40-0.87; P = .007), and indwelling pleural catheters (HR = 0.3; 95% CI, 0.13-0.71; P = .006) were each associated with improvements in OS. CONCLUSION: Despite the small incremental improvements in survival shown by the three interventions we examined, prognosis remains guarded for MPM patients. Better modalities of management are needed.

The Goto-Kakizaki rat is a spontaneous prototypical rodent model of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is characterized by an oligo-anovulation, hyperandrogenism and polycystic ovarian morphology combined with major metabolic disturbances. However, despite the high prevalence and the human and economic consequences of this syndrome, its etiology remains unknown. In this study, we show that female Goto-Kakizaki (GK) rats, a type 2 diabetes mellitus model, encapsulate naturally all the reproductive and metabolic hallmarks of lean women with PCOS at puberty and in adulthood. The analysis of their gestation and of their fetuses demonstrates that this PCOS-like phenotype is developmentally programmed. GK rats also develop features of ovarian hyperstimulation syndrome. Lastly, a comparison between GK rats and a cohort of women with PCOS reveals a similar reproductive signature. Thus, this spontaneous rodent model of PCOS represents an original tool for the identification of the mechanisms involved in its pathogenesis and for the development of novel strategies for its treatment.

Borderline ovarian tumors: Guidelines from the French national college of obstetricians and gynecologists (CNGOF).

It is recommended to classify Borderline Ovarian Tumors (BOTs) according to the WHO classification. Transvaginal and suprapubic ultrasonography are recommended for the analysis of an ovarian mass (Grade A). In case of an undetermined ovarian lesion on ultrasonography, it is recommended to perform a pelvic MRI (Grade A) with a score for malignancy (ADNEX MR/O-RADS) (Grade C) included in the report and to formulate a histological hypothesis (Grade C). Pelvic MRI is recommended to characterize a tumor suspected of being BOT (Grade C). It is recommended to evaluate serum levels of HE4 and CA125 and to use the ROMA score for the diagnosis of indeterminate ovarian mass on imaging (grade A). If there is a suspicion of a mucinous BOT on imaging, serum levels of CA 19-9 may be proposed (Grade C). For Early Stages (ES) of BOT, if surgery without risk of tumor rupture is possible, laparoscopy with protected extraction is recommended over laparotomy (Grade C). For treatment of a bilateral serous ES BOT with a strategy to preserve fertility and/or endocrine function, bilateral cystectomy is recommended where possible (Grade B). For mucinous BOTs with a treatment strategy of fertility and/or endocrine function preservation, unilateral salpingo-oophorectomy is recommended (grade C). For mucinous BOTs treated by initial cystectomy, unilateral salpingo-oophorectomy is recommended (grade C). For serous or mucinous ES BOTs, routine hysterectomy is not recommended (Grade C). For ES BOTs, lymphadenectomy is not recommended (Grade C). For ES BOTs, appendectomy is recommended only in case of a macroscopically pathological appendix (Grade C). Restaging surgery is recommended in cases of serous BOTs with micropapillary architecture and an incomplete abdominal cavity inspection during initial surgery (Grade C). Restaging surgery is recommended for mucinous BOTs after initial cystectomy or in cases where the appendix was not examined (Grade C). If restaging surgery is decided for ES BOTs, the following procedures should be performed: peritoneal washing (grade C), omentectomy (grade B), complete exploration of the abdominal cavity with peritoneal biopsies (grade C), visualization of the appendix and appendectomy in case of a pathological macroscopic appearance (grade C) as well as unilateral salpingo-oophorectomy in case of a mucinous BOT initially treated by cystectomy (grade C). In advanced stages (AS) of BOT, it is not recommended to perform a lymphadenectomy as a routine procedure (Grade C). For AS BOT in a patient with a desire to fall pregnant, conservative treatment involving preservation of the uterus and all or part of the ovary may be proposed (Grade C). Restaging surgery aimed at removing all lesions, not performed initially, is recommended for AS BOTs (Grade C). After treatment, follow-up for a duration greater than 5 years is recommended due to the median recurrence time of BOTs (Grade B). It is recommended that a systematic clinical examination be carried out during follow-up of a treated BOT (Grade B). If the determination of tumor markers is normal preoperatively, the routine dosage of tumor markers in BOT follow-up is not recommended (Grade C). In case of an initial elevation in serum CA 125 levels, it is recommended to monitor CA 125 during follow up (Grade B). In case of conservative treatment, it is recommended to use transvaginal and transabdominal ultrasound during follow up of a treated BOT (Grade B). In the event of a BOT recurrence in a woman of childbearing age, a second conservative treatment may be proposed (Grade C). A consultation with a physician specialized in Assisted Reproductive Technique (ART) should be offered in the case of BOTs in women of childbearing age (Grade C). When possible, a conservative surgical strategy is recommended to preserve fertility in women of childbearing age (Grade C). In the case of optimally treated BOT, there is no evidence to contraindicate the use of ART. The use of hormonal contraception after serous or mucinous BOT is not contraindicated (Grade C). After management of mucinous BOT, for women under 45 years, given the benefit of Hormonal Replacement Therapy (HRT) on cardiovascular and bone risks, and the lack of hormone sensitivity of mucinous BOTs, it is recommended to offer HRT (Grade C). Over 45 years of age, HRT can be prescribed in case of a climacteric syndrome after individual benefit to risk assessment (Grade C).

New Anti-Müllerian Hormone Target Genes Involved in Granulosa Cell Survival in Women With Polycystic Ovary Syndrome.

PURPOSE: A protective effect of anti-Müllerian hormone (AMH) on follicle atresia was recently demonstrated using long-term treatments, but this effect has never been supported by mechanistic studies. This work aimed to gain an insight into the mechanism of action of AMH on follicle atresia and on how this could account for the increased follicle pool observed in women with polycystic ovary syndrome (PCOS). METHODS: In vivo and in vitro experiments were performed to study the effects of AMH on follicle atresia and on the proliferation and apoptosis of granulosa cells (GCs). RNA-sequencing was carried out to identify new AMH target genes in GCs. The expression of some of these genes in GCs from control and PCOS women was compared using microfluidic real time quantitative RT-PCR. RESULTS: A short-term AMH treatment prevented follicle atresia in prepubertal mice. Consistent with this result, AMH inhibited apoptosis and promoted proliferation of different models of GCs. Moreover, integrative biology analyses of 965 AMH target genes identified in 1 of these GC models, confirmed that AMH had initiated a gene expression program favoring cell survival and proliferation. Finally, on 43 genes selected among the most up- and down-regulated AMH targets, 8 were up-regulated in GCs isolated from PCOS women, of which 5 are involved in cell survival. MAIN CONCLUSIONS: Our results provide for the first time cellular and molecular evidence that AMH protects follicles from atresia by controlling GC survival and suggest that AMH could participate in the increased follicle pool of PCOS patients.

Borderline ovarian tumors: French guidelines from the CNGOF. Part 1. Epidemiology, biopathology, imaging and biomarkers.

The incidence (rate per 100 000) of borderline ovarian tumors (BOTs) increases progressively with age, starting at 15-19 years and peaking at around 4.5 cases per 100 000 at an age of 55-59 years (LE3) with a median age of 46 years. The five year survival for FIGO stages I, II, III and IV is 99.7 % (95 % CI: 96.2-100 %), 99.6 % (95 % CI: 92.6-100 %), 95.3 % (95 % CI: 91.8-97.4 %) and 77.1 % (95 % CI: 58.0-88.3 %), respectively (LE3). An epidemiological association exists between the individual risk of BOT and family history of BOT and certain other cancers (pancreatic, lung, bone, leukemia) (LE3), a personal history of benign ovarian cyst (LE2), a personal history of tubo-ovarian infection (LE3), the use of a levonorgestrel intrauterine device (LE3), oral contraceptive use (LE3), multiparity (LE3), Hormonal replacement therapy (LE3), high consumption of Coumestrol (LE4), medical treatment for infertility with progesterone (LE3) and non-steroidal anti-inflammatory drug use (LE3). Screening for BOTs is not recommended for patients (Grade C). The overall risk of recurrence of BOTs varies between 2% and 24 %, with an overall survival greater than 94 % at 10 years, and the risk of an invasive recurrence of a BOT ranges from 0.5 % to 3.8 %. The use of scores and nomograms can be useful in assessing the risk of recurrence, and providing patients with information (Grade C). The WHO classification is recommended for classifying BOTs. It is recommended that the presence of a microinvasive focus (<5 mm) and microinvasive carcinoma (<5 mm with an atypical nuclei and a desmoplastic stroma reaction) within a BOT be reported. In cases of serous BOT, it is recommended to specify the classic histological subtype or micropapillary / cribriform type (Grade C). When confronted with a BOT, it is recommended that the invasive or non-invasive nature of peritoneal implants can be investigated based solely on the invasion and destruction of underlying adipose or peritoneal tissue which has a desmoplastic stromal reaction where in contact with the invasive clusters (Grade B). For bilateral mucinous BOTs and / or in cases with peritoneal implants or peritoneal pseudomyxoma, it is recommended to also look for a primitive digestive or pancreato-biliary cancer (Grade C). It is recommended to sample ovarian tumors suspected of being BOTs by focusing samples on vegetations and solid components, with at least 1 sample per cm in tumors with a size less than 10 cm and 2 samples per cm in tumors with a size greater than 10 cm (Grade C). In cases of BOTs and in the absence of macroscopic omental involvement after careful macroscopic examination, it is recommended to perform at least 4-6 systematic sampling blocks and to include all peritoneal implants (Grade C). It is recommended to consult an expert pathologist in gynecology when a BOT suspicion requires intraoperative extemporaneous histology (grade C). Endo-vaginal and suprapubic ultrasonography are recommended for the analysis of an ovarian mass (Grade A). In case of an undetermined ovarian lesion on ultrasonography, it is recommended that a pelvic MRI be performed (Grade A). To analyze an adnexal mass with MRI, it is recommended to use an MRI protocol with T2, T1, T1 Fat Sat, dynamic and diffusion sequences as well as gadolinium injection (Grade B). To characterize an adnexal mass with MRI, it is recommended to include a score system for malignancy (ADNEX MR/O-RADS) (Grade C) in the report and to formulate a histological hypothesis (Grade C). Pelvic MRI is recommended to characterize a tumor suspected of being a BOT (Grade C). Macroscopic MRI features should be analyzed to differentiate BOT subtypes (Grade C). Pelvic ultrasound is the first-line examination for the detection and characterization of adnexal masses during pregnancy (Grade C). Pelvic MRI is recommended from 12 weeks of gestation in case of an indeterminate adnexal mass and should provide a diagnostic score (Grade C). Gadolinium injection must be minimized as fetal impairment has been proven (Grade C). It is recommended that serum levels of HE4 and CA125 be evaluated and that the ROMA score for the diagnosis of an indeterminate ovarian mass on imaging be used (grade A). In case of suspicion of a mucinous BOT on imaging, dosage of serum levels of CA 19-9 can be considered (Grade C). If the determination of tumor markers is normal preoperatively, routine dosage of tumor markers in BOT follow-up is not recommended (Grade C). In case of preoperative elevation in tumor markers, the determination of serum CA 125 levels is recommended in the follow-up of BOT (Grade B). When conservative treatment of a BOT has been adopted, the use of endovaginal and transabdominal ultrasonography is recommended during follow-up (Grade B).

Use of the EFI score in endometriosis-associated infertility: A cost-effectiveness study.

BACKGROUND: The management of endometriosis-related infertility is still under debate. The Endometriosis Fertility Index (EFI) score is performant to predict the occurrence of a spontaneous pregnancy following surgery, but was not evaluated in a cost-effectiveness perspective. Our objective was to quantify fertility outcomes, and costs of different care pathways for endometriosis-associated infertility after primary surgery, with a stratification on the EFI score. STUDY DESIGN: We conducted a cost-effectiveness analysis based on a decision-tree model in a Tertiary-care university hospital. Extracted form a prospectively maintained database, 608 patients with endometriosis-associated infertility, who underwent laparoscopic treatment with an evaluation of the EFI score, were discriminated between different strategies: natural conception, immediate IVF-ICSI, delayed IVF-ICSI. The pregnancy rate and the live birth rate were the effectiveness outcomes. We considered direct and indirect costs in each strategies. The analysis was stratified according to the EFI score. RESULTS: After surgery, 163 women with immediate IVF-ICSI (strategy I) were compared with 445 women who had natural conception attempts during a year (strategy II). After a year failure of natural conception attempts, 133 women continuing natural conception attempts (strategy III) were compared with 168 women who had delayed IVF-ICSI (strategy IV). The respective PR and LBR were 62.6 % and 52.1 % for strategy I, and 32.4 % and 23.8 % for strategy II. Compared to strategy II, strategy I was more costly and more effective (Incremental Cost Effectiveness Ratio (ICER): 31,469 €/pregnancy and 33,568 €/live birth)). No added benefit was observed for patients in strategy I with an EFI score [0-3] after two IVF-ICSI cycles. Strategy III was strongly dominant versus strategy IV for patients with an EFI score [9-10]. Compared to strategy III, strategy VI was more costly and more effective (ICER: 79,674 €/pregnancy, 53,188 €/pregnancy and 27,748 €/pregnancy respectively for patients with an EFI score [7-8], [4-6] and [0-3]). CONCLUSION: Immediate IVF-ICSI after surgery is effective but associated with substantial costs for the healthcare system. Taking into account healthcare costs, the EFI is a useful score for helping a couple decide between different care pathways -natural conception, immediate or delayed IVF-ICSI- after surgery for endometriosis-associated infertility.

Trapeziometacarpal total joint replacement as an alternative to trapeziectomy depends on trapezium height: Retrospective study of 67 patients.

Surgical indications for trapeziometacarpal (TMC) total joint replacement for thumb basal joint osteoarthritis (OA) are increasing. However, complications following this procedure are not insignificant. To avoid complications, preoperative planning with measurement of trapezium height is indicated to ensure a cup is not implanted in the trapezium if its height is less than 8 millimeters. The objective of our study was to analyze a series of preoperative radiographs of patients managed by trapeziectomy and suspensionplasty in our department, and to assess the possibility of a surgical alternative-total joint replacement-based on the trapezium's height. We also wanted to determine whether radiological height was influenced by the radiological progression of the thumb OA. A single-center retrospective study based on available medical records was conducted. The patients included had TMC OA refractory to conservative treatment and were managed surgically by trapeziectomy and suspensionplasty between 2012 and 2018. Sixty-seven patients were eligible. Based on the Eaton-Littler classification of radiological TMC OA, our case series had 0% (n=0) stage I, 36% (n=24) stage II, 42% (n=28) stage III and 22% (n=15) stage IV findings. We measured the radiological trapezium height on AP and lateral views as described by Kapandji. These were 10.6mm and 10.8mm for stage II, 9.6mm and 8.9mm for stage III, 8.6mm and 7.8mm for stage IV, respectively. Eighty-six percent of patients had a trapezium height suitable for total joint replacement. The radiological height decreased significantly with the OA stage. At stage IV, the average height fell below the 8-mm threshold, compromising the surgical indication for total arthroplasty.

[Borderline Ovarian Tumours: CNGOF Guidelines for Clinical Practice - Short Text]. / Tumeurs frontières de l'ovaire. Recommandations pour la pratique clinique du CNGOF ­ Texte court.

This work was carried out under the aegis of the CNGOF (Collège national des gynécologues et obstétriciens français) and proposes guidelines based on the evidence available in the literature. The objective was to define the diagnostic and surgical management strategy, the fertility preservation and surveillance strategy in Borderline Ovarian Tumor (BOT). No screening modality can be proposed in the general population. An expert pathological review is recommended in case of doubt concerning the borderline nature, the histological subtype, the invasive nature of the implant, for all micropapillary/cribriform serous BOT or in the presence of peritoneal implants, and for all mucinous or clear cell tumors (grade C). Macroscopic MRI analysis should be performed to differentiate the different subtypes of BOT: serous, seromucinous and mucinous (intestinal type) (grade C). If preoperative biomarkers are normal, follow up of biomarkers is not recommended (grade C). In cases of bilateral early serous BOT with a desire to preserve fertility and/or endocrine function, it is recommended to perform a bilateral cystectomy if possible (grade B). In case of early mucinous BOT, with a desire to preserve fertility and/or endocrine function, it is recommended to perform a unilateral adnexectomy (grade C). Secondary surgical staging is recommended in case of serous BOT with micropapillary appearance and uncomplete inspection of the abdominal cavity during initial surgery (grade C). For early-stage serous or mucinous BOT, it is not recommended to perform a systematic hysterectomy (grade C). Follow up after BOT must be pursued for more than 5 years (grade B). Conservative treatment involving at least the conservation of the uterus and a fragment of the ovary in a patient wishing to conceive may be proposed in advanced stages of BOT (grade C). A new surgical treatment that preserves fertility after a first non-invasive recurrence may be proposed in women of childbearing age (grade C). It is recommended to offer a specialized consultation for Reproductive Medicine when diagnosing BOT in a woman of childbearing age. Hormonal contraceptive use after serous or mucinous BOT is not contraindicated (grade C).

[Borderline Ovarian Tumours: CNGOF Guidelines for Clinical Practice - Fertility]. / Tumeurs frontières de l'ovaire. Recommandations pour la pratique clinique du CNGOF ­ Fertilité.

OBJECTIVES: Borderline ovarian tumours (BOT) represent around 15% of all ovarian neoplasms and are more likely to be diagnosed in women of reproductive age. Overall, given the epidemiological profile of BOT and their favourable prognosis, ovarian function and fertility preservation should be systematically considered in patients presenting these lesions. METHODS: The research strategy was based on the following terms: borderline ovarian tumour, fertility, fertility preservation, infertility, fertility-sparing surgery, in vitro fertilization, ovarian stimulation, oocyte cryopreservation, using PubMed, in English and French. RESULTS AND CONCLUSIONS: Fertility counselling should become an integral part of the clinical management of women with BOT. Patients with BOT should be informed that surgical management of BOT may cause damage ovarian reserve and/or peritoneal adhesions. Nomogram to predict recurrence, ovarian reserve markers and fertility explorations should be used to provide a clear and relevant information about the risk of infertility in patients with BOT. Fertility-sparing surgery should be considered for young women who wish preserving their fertility when possible. There is insufficient evidence to claim a causal relation between controlled ovarian stimulation (COS) and BOT. However, in case of poor prognosis factors, the use of COS should be considered cautiously through a multidisciplinary approach. In case of infertility after surgery for BOT, COS can be performed without delay, once histopathological diagnosis of BOT is confirmed. There is insufficient consistent evidence that fertility drugs and COS increase the risk of recurrence of BOT after conservative management. The conservative surgical treatment can be associated to oocyte cryopreservation considering the high risk of recurrence of the disease. In women with BOT recurrence in a single ovary and in women with bilateral ovarian involvement when the conservative management is not possible, other fertility preservation strategies are available, but still experimental.

Outcomes of fertility preservation in women with endometriosis: comparison of progestin-primed ovarian stimulation versus antagonist protocols.

BACKGROUND: PPOS protocols, initially described for FP in women with cancer, have many advantages compared to antagonist protocols. PPOS protocols were not evaluated for women with endometriosis. The objective of the study was to describe fertility preservation outcomes in women with endometriosis and to compare an antagonist protocol with a Progestin-Primed Ovarian Stimulation (PPOS) protocol. METHOD: We conducted a prospective cohort study associated with a cost-effectiveness analysis in a tertiary-care university hospital. The measured outcomes included the numbers of retrieved and vitrified oocytes, and direct medical costs. In the whole population, unique and multiple linear regressions analysis were performed to search for a correlation between individual characteristics and the number of retrieved oocyte. RESULTS: We included 108 women with endometriosis who had a single stimulation cycle performed with either an antagonist or a PPOS protocol. Overall, 8.1 ± 6.6 oocytes were retrieved and 6.4 ± 5.6 oocytes vitrified per patient. In the multiple regression model, age (p = 0.001), prior ovarian surgery (p = 0.035), and anti-Mullerian hormone level (p = 0.001) were associated with the number of retrieved oocytes. Fifty-four women were stimulated with an antagonist protocol, and 54 with a PPOS protocol. A mean of 7.9 ± 7.4 oocytes were retrieved in the antagonist group and 8.2 ± 5.6 in the PPOS group (p = 0.78). A mean of 6.4 ± 6.4 oocytes were vitrified in the antagonist group and 6.4 ± 4.7 in the PPOS group (p = 1). In the cost-effectiveness analysis, the PPOS protocol was strongly dominant over the antagonist protocol. CONCLUSION: Fertility preservation procedures are feasible and effective for patients affected by endometriosis. Antagonist and PPOS protocols were associated with similar results but the medico-economic analysis was in favor of PPOS protocols.

MRI monitoring of temperature and displacement for transcranial focus ultrasound applications.

BACKGROUND: Transcranial focus ultrasound applications applied under MRI-guidance benefit from unrivaled monitoring capabilities, allowing the recording of real-time anatomical information and biomarkers like the temperature rise and/or displacement induced by the acoustic radiation force. Having both of these measurements could allow for better targeting of brain structures, with improved therapy monitoring and safety. METHOD: We investigated the use of a novel MRI-pulse sequence described previously in Bour et al., (2017) to quantify both the displacement and temperature changes under various ultrasound sonication conditions and in different regions of the brain. The method was evaluated in vivo in a non-human primate under anesthesia using a single-element transducer (f = 850 kHz) in a setting that could mimic clinical applications. Acquisition was performed at 3 T on a clinical imaging system using a modified single-shot gradient echo EPI sequence integrating a bipolar motion-sensitive encoding gradient. Four slices were acquired sequentially perpendicularly or axially to the direction of the ultrasound beam with a 1-Hz update frequency and an isotropic spatial resolution of 2-mm. A total of twenty-four acquisitions were performed in three different sets of experiments. Measurement uncertainty of the sequence was investigated under different acoustic power deposition and in different regions of the brain. Acoustic simulation and thermal modeling were performed and compared to experimental data. RESULTS: The sequence simultaneously provides relevant information about the focal spot location and visualization of heating of brain structures: 1) The sequence localized the acoustic focus both along as well as perpendicular to the ultrasound direction. Tissue displacements ranged from 1 to 2 µm. 2) Thermal rise was only observed at the vicinity of the skull. Temperature increase ranged between 1 and 2 °C and was observed delayed relative the sonication due to thermal diffusion. 3) The fast frame rate imaging was able to highlight magnetic susceptibility artifacts related to breathing, for the most caudal slices. We demonstrated that respiratory triggering successfully restored the sensitivity of the method (from 0.7 µm to 0.2 µm). 4) These results were corroborated by acoustic simulations. CONCLUSIONS: The current rapid, multi-slice acquisition and real-time implementation of temperature and displacement visualization may be useful in clinical practices. It may help defining operational safety margins, improving therapy precision and efficacy. Simulations were in good agreement with experimental data and may thus be used prior treatment for procedure planning.

Predicting the likelihood of a live birth for women with endometriosis-related infertility.

OBJECTIVE: Endometriosis affects 10% of women in reproductive age and alters fertility. Its management is still debated notably the timing of surgery and ART in infertility. Several tools have been created to guide the practitioner and the couple yet many limitations persist. The objective is to create a nomogram to predict the likelihood of a live birth after surgery followed by assisted reproductive technology (ART) for patients with endometriosis-related infertility. STUDY DESIGN: All women in a public university hospital who attempted to conceive by ART after surgery for endometriosis-related infertility from 2004 to 2016 were included. We created a model using multivariable linear regression based on a retrospective database. RESULT: Of the 297 women included, 171 (57.6%) obtained a live birth. Age, duration of infertility, number of ICSI-IVF cycles, ovarian reserve and the revised American Fertility Society (rAFS) score were included in the nomogram. The predictive model had an area under the curve (AUC) of 0.77 (95% CI, 0.75-0.79) and was well calibrated. The external validation of the model was achieved with an AUC of 0.71 (95% CI, 0.69-0.73) and calibration was good. The staging accuracy according to AUC criteria for the nomogram compared to the currently used Endometriosis Infertility Index to predict live births were 0.77 (95% CI, 0.75-0.79) and 0.60 (95% CI: 0.57-0.63), respectively. CONCLUSION: This simple tool appears to accurately predict the likelihood of a live birth for a patient undergoing ART after surgery for endometriosis-related infertility. It could be used to counsel patients in their choice between spontaneous versus ART conception, or oocyte donation.

Proportion of Cytotoxic Peripheral Blood Natural Killer Cells and T-Cell Large Granular Lymphocytes in Recurrent Miscarriage and Repeated Implantation Failure: Case-Control Study and Meta-analysis.

We aimed to compare the proportion of peripheral blood natural killer (NK) cells (CD3-CD56+) and T-cell large granular lymphocytes (CD8+CD57+) during preconception in a homogenous group of women with unexplained well-defined recurrent miscarriage (RM) and repeated implantation failure (RIF) vs healthy controls in relation to pregnancy outcomes. This case-control study followed by a literature review and meta-analysis was conducted in three university hospitals. Patients and controls were consecutively recruited from December 2015 to October 2017. In total, 115 women were included in the study: 54 with RM, 41 with RIF and 20 healthy controls with ≥ 2 term births. Percentages of CD3-CD56+ and CD8+CD57+ cells and sub-populations of CD3-CD56+ cells did not differ between cases and controls. The results for women with subsequent miscarriage did not differ from those with live births. The meta-analysis of the literature showed higher NK-cell proportions in RM [mean difference 3.47 (95% CI 2.94-4.00); p < 0.001] and RIF [mean difference 1.64 (95% CI 0.82-2.45); p < 0.001] than controls. However, the heterogeneity between the different studies was high. The proportion of peripheral blood CD3-CD56+ and CD8+CD57+ cells in the preconception period does not reflect the risk of implantation failure or miscarriage and should not be recommended indicators for the management of RM and RIF. Further prospective large studies are needed to develop a reliable peripheral blood marker of immune deregulation.