[Fetal death: Expert consensus from the College of French Gynecologists and Obstetricians]. / Mort fœtale : consensus formalisé d'experts du Collège national des gynécologues-obstétriciens français.

Fetal death is defined as the spontaneous cessation of cardiac activity after fourteen weeks of amenorrhea. In France, the prevalence of fetal death after 22 weeks is between 3.2 and 4.4/1000 births. Regarding the prevention of fetal death in the general population, it is not recommended to counsel for rest and not to prescribe vitamin A, vitamin D nor micronutrient supplementation for the sole purpose of reducing the risk of fetal death (Weak recommendations; Low quality of evidence). It is not recommended to prescribe aspirin (Weak recommendation; Very low quality of evidence). It is recommended to offer vaccination against influenza in epidemic periods and against SARS-CoV-2 (Strong recommendations; Low quality of evidence). It is not recommended to systematically look for nuchal cord encirclements during prenatal screening ultrasounds (Strong Recommendation; Low Quality of Evidence) and not to perform systematic antepartum monitoring by cardiotocography (Weak Recommendation; Very Low Quality of Evidence). It is not recommended to ask women to perform an active fetal movement count to reduce the risk of fetal death (Strong Recommendation; High Quality of Evidence). Regarding evaluation in the event of fetal death, it is suggested that an external fetal examination be systematically offered (Expert opinion). It is recommended that a fetopathological and anatomopathological examination of the placenta be carried out to participate in cause identification (Strong Recommendation. Moderate quality of evidence). It is recommended that chromosomal analysis by microarray testing be performed rather than conventional karyotype, in order to be able to identify a potentially causal anomaly more frequently (Strong Recommendation, moderate quality of evidence); to this end, it is suggested that postnatal sampling of the placental fetal surface for genetic purposes be preferred (Expert Opinion). It is suggested to test for antiphospholipid antibodies and systematically perform a Kleihauer test and a test for irregular agglutinins (Expert opinion). It is suggested to offer a summary consultation, with the aim of assessing the physical and psychological status of the parents, reporting the results, discussing the cause and providing information on monitoring for a subsequent pregnancy (Expert opinion). Regarding announcement and support, it is suggested to announce fetal death without ambiguity, using simple words and adapting to each situation, and then to support couples with empathy in the various stages of their care (Expert opinion). Regarding management, it is suggested that, in the absence of a situation at risk of disseminated intravascular coagulation or maternal vitality, the patient's wishes should be taken into account when determining the time between the diagnosis of fetal death and induction of birth. Returning home is possible if it's the patient wish (Expert opinion). In all situations excluding maternal life-threatening emergencies, the preferred mode of delivery is vaginal delivery, regardless the history of cesarean section(s) history (Expert opinion). In the event of fetal death, it is recommended that mifepristone 200mg be prescribed at least 24hours before induction, to reduce the delay between induction and delivery (Low recommendation. Low quality of evidence). There are insufficient data in the literature to make a recommendation regarding the route of administration (vaginal or oral) of misoprostol, neither the type of prostaglandin to reduce induction-delivery time or maternal morbidity. It is suggested that perimedullary analgesia be introduced at the start of induction if the patient asks, regardless of gestational age. It is suggested to prescribe cabergoline immediately in the postpartum period in order to avoid lactation, whatever the gestational age, after discussing the side effects of the treatment with the patient (Expert opinion). The risk of recurrence of fetal death after unexplained fetal death does not appear to be increased in subsequent pregnancies, and data from the literature are insufficient to make a recommendation on the prescription of aspirin. In the event of a history of fetal death due to vascular issues, low-dose aspirin is recommended to reduce perinatal morbidity, and should not be combined with heparin therapy (Low recommendation, very low quality of evidence). It is suggested not to recommend an optimal delay before initiating another pregnancy just because of the history of fetal death. It is suggested that the woman and co-parent be informed of the possibility of psychological support. Fetal heart rate monitoring is not indicated solely because of a history of fetal death. It is suggested that delivery not be systematically induced. However, induction can be considered depending on the context and parental request. The gestational age will be discussed, taking into account the benefits and risks, especially before 39 weeks. If a cause of fetal death is identified, management will be adapted on a case-by-case basis (expert opinion). In the event of fetal death occurring in a twin pregnancy, it is suggested that the surviving twin be evaluated as soon as the diagnosis of fetal death is made. In the case of dichorionic pregnancy, it is suggested to offer ultrasound monitoring on a monthly basis. It is suggested not to deliver prematurely following fetal death of a twin. If fetal death occurs in a monochorionic twin pregnancy, it is suggested to contact the referral competence center, in order to urgently look for signs of acute fetal anemia on ultrasound in the surviving twin, and to carry out weekly ultrasound monitoring for the first month. It is suggested not to induce birth immediately.

[Development of a measuring tool for performance anxiety in obstetrics]. / Développement d'un outil d'évaluation de l'anxiété de performance en obstétrique.

OBJECTIVE: Developing a measuring tool for physician's performance anxiety during obstetrical procedures, as a self-administered questionnaire. METHODS: We used the Delphi method. First, we did a literature review to identify the items to submit for the first round. A panel of experts was asked to rate the relevance of items from one to six. For the first round of Delphi, items were retained if more than 70% of respondents assigned a five or six rating. Items were excluded if more than 70% of respondents assigned a one or two rating. All the other items, plus those suggested by the panel, were submitted to a second round of Delphi. The same item selection conditions were applied to the second round. RESULTS: The overall response rate to the Delphi was 79% (19 respondents). At the end of the first round, 14 items were consensually relevant, no item was consensually irrelevant. For the second round, the 18 items that did not find consensus and seven new items suggested by the experts in the first round were submitted. At the end of the second round, nine items were retained by consensus as relevant. CONCLUSION: This study defined by consensus 23 items for a self-questionnaire to measure specific performance anxiety in obstetrics divided into five dimensions: perceived stress, assessment of the risk of complications, medico-legal risk, impact of the healthcare team and peers, self-confidence and decision-making confidence. We intend to validate this tool in real population.

Identification of constrained sequence elements across 239 primate genomes.

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3-9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.

Impact of discontinuing oxytocin in active labour on neonatal morbidity: an open-label, multicentre, randomised trial.

BACKGROUND: Oxytocin is effective in reducing labour duration but can be associated with fetal and maternal complications that could potentially be reduced by discontinuing the treatment during labour. We aimed to assess the impact of discontinuing oxytocin during active labour on neonatal morbidity. METHODS: STOPOXY was a multicentre, randomised, open-label, controlled, superiority trial conducted in 21 maternity units in France. Participants who received oxytocin before 4 cm dilation were randomly assigned 1:1 to either discontinuous oxytocin (oxytocin infusion stopped beyond a cervical dilation equal to or greater than 6 cm) or continuous oxytocin (administration of oxytocin continued until delivery). Randomisation was stratified by centre and parity. The primary outcome, neonatal morbidity, was assessed at birth using a composite variable defined by an umbilical arterial pH at birth less than 7·10, a base excess greater than 10 mmol/L, umbilical arterial lactates greater than 7 mmol/L, a 5-min Apgar score less than 7, or admission to the neonatal intensive care unit. Efficacy and safety was assessed in participants who were randomly assigned (excluding those who withdrew consent or were deemed ineligible after randomisation) and had reached a cervical dilation of at least 6 cm. This trial is registered with ClinicalTrials.gov, NCT03991091. FINDINGS: Of 2459 participants randomly assigned between Jan 13, 2020, and Jan 24, 2022, 2170 were eligible to receive the intervention and were included in the final modified intention-to-treat analysis. The primary outcome occurred for 102 (9·6%) of 1067 participants (95% CI 7·9 to 11·5) in the discontinuous oxytocin group and for 101 (9·2%) of 1103 participants (7·6 to 11·0) in the continuous oxytocin group; absolute difference 0·4% (95% CI -2·1 to 2·9); relative risk 1·0 (95% CI 0·8 to 1·4). There were no clinically significant differences in adverse events between the two groups of the safety population. INTERPRETATION: Among participants receiving oxytocin in early labour, discontinuing oxytocin when the active phase is reached does not clinically or statistically significantly reduce neonatal morbidity compared with continuous oxytocin. FUNDING: French Ministry of Health and the Département de la Recherche Clinique et du Développement de l'Assistance Publique-Hôpitaux de Paris.

First-line durvalumab and tremelimumab with chemotherapy in RAS-mutated metastatic colorectal cancer: a phase 1b/2 trial.

Although patients with microsatellite instable metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single-arm, phase 1b/2 MEDITREME trial evaluated the safety and efficacy of durvalumab plus tremelimumab combined with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable metastatic CRC. Safety was the primary objective of phase Ib; no safety issue was observed. The phase 2 primary objective of efficacy in terms of 3-month progression-free survival (PFS) in patients with MSS tumors was met, with 3-month PFS of 90.7% (95% confidence interval (CI): 79.2-96%). For secondary objectives, response rate was 64.5%; median PFS was 8.2 months (95% CI: 5.9-8.6); and overall survival was not reached in patients with MSS tumors. We observed higher tumor mutational burden and lower genomic instability in responders. Integrated transcriptomic analysis underlined that high immune signature and low epithelial-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor-specific T cell response associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC. Clinicaltrials.gov identifier: NCT03202758 .

Effectiveness and Costs of Molecular Screening and Treatment for Bacterial Vaginosis to Prevent Preterm Birth: The AuTop Randomized Clinical Trial.

Importance: Bacterial vaginosis (BV) is a well-known risk factor for preterm birth. Molecular diagnosis of BV is now available. Its impact in the screening and treatment of BV during pregnancy on preterm births has not been evaluated to date. Objective: To evaluate the clinical and economic effects of point-of-care quantitative real-time polymerase chain reaction screen and treat for BV in low-risk pregnant women on preterm birth. Design, Setting, and Participants: The AuTop trial was a prospective, multicenter, parallel, individually randomized, open-label, superiority trial conducted in 19 French perinatal centers between March 9, 2015, and December 18, 2017. Low-risk pregnant women before 20 weeks' gestation without previous preterm births or late miscarriages were enrolled. Data were analyzed from October 2021 to November 2022. Interventions: Participants were randomized 1:1 to BV screen and treat using self-collected vaginal swabs (n = 3333) or usual care (n = 3338). BV was defined as Atopobium vaginae (Fannyhessea vaginae) load of 108 copies/mL or greater and/or Gardnerella vaginalis load of 109 copies/mL or greater, using point-of-care quantitative real-time polymerase chain reaction assays. The control group received usual care with no screening of BV. Main Outcomes and Measures: Overall rate of preterm birth before 37 weeks' gestation and total costs were calculated in both groups. Secondary outcomes were related to treatment success as well as maternal and neonate health. Post hoc subgroup analyses were conducted. Results: Among 6671 randomized women (mean [SD] age, 30.6 [5.0] years; mean [SD] gestational age, 15.5 [2.8] weeks), the intention-to-treat analysis of the primary clinical and economic outcomes showed no evidence of a reduction in the rate of preterm birth and total costs with the screen and treat strategy compared with usual care. The rate of preterm birth was 3.8% (127 of 3333) in the screen and treat group and 4.6% (153 of 3338) in the control group (risk ratio [RR], 0.83; 95% CI, 0.66-1.05; P = .12). On average, the cost of the intervention was €203.6 (US $218.0) per participant, and the total average cost was €3344.3 (US $3580.5) in the screen and treat group vs €3272.9 (US $3504.1) in the control group, with no significant differences being observed. In the subgroup of nulliparous women (n = 3438), screen and treat was significantly more effective than usual care (RR, 0.62; 95% CI, 0.45-0.84; P for interaction = .003), whereas no statistical difference was found in multiparous (RR, 1.30; 95% CI, 0.90-1.87). Conclusion and Relevance: In this clinical trial of pregnant women at low risk of preterm birth, molecular screening and treatment for BV based on A vaginae (F vaginae) and/or G vaginalis quantification did not significantly reduce preterm birth rates. Post hoc analysis suggests a benefit of screen and treat in low-risk nulliparous women, warranting further evaluation in this group. Trial Registration: ClinicalTrials.gov Identifier: NCT02288832.

Adjuvant endocrine therapy uptake, toxicity, quality of life, and prediction of early discontinuation.

BACKGROUND: Many patients receiving adjuvant endocrine therapy (ET) for breast cancer experience side effects and reduced quality of life (QoL) and discontinue ET. We sought to describe these issues and develop a prediction model of early discontinuation of ET. METHODS: Among patients with hormone receptor-positive and HER2-negative stage I-III breast cancer of the Cancer Toxicities cohort (NCT01993498) who were prescribed adjuvant ET between 2012 and 2017, upon stratification by menopausal status, we evaluated adjuvant ET patterns including treatment change and patient-reported discontinuation and ET-associated toxicities and impact on QoL. Independent variables included clinical and demographic features, toxicities, and patient-reported outcomes. A machine-learning model to predict time to early discontinuation was trained and evaluated on a held-out validation set. RESULTS: Patient-reported discontinuation rate of the first prescribed ET at 4 years was 30% and 35% in 4122 postmenopausal and 2087 premenopausal patients, respectively. Switching to a new ET was associated with higher symptom burden, poorer QoL, and higher discontinuation rate. Early discontinuation rate of adjuvant ET before treatment completion was 13% in postmenopausal and 15% in premenopausal patients. The early discontinuation model obtained a C index of 0.62 in the held-out validation set. Many aspects of QoL, most importantly fatigue and insomnia (European Organization for Research and Treatment of Cancer QoL questionnaire 30), were associated with early discontinuation. CONCLUSION: Tolerability and adherence to ET remains a challenge for patients who switch to a second ET. An early discontinuation model using patient-reported outcomes identifies patients likely to discontinue their adjuvant ET. Improved management of toxicities and novel more tolerable adjuvant ETs are needed for maintaining patients on treatment.

Standardized Stretching Postural postures to treat low-back pain in pregnancy: the GEMALODO randomized clinical trial.

BACKGROUND: Two-thirds of pregnant women suffer from low-back pain during pregnancy, which leads to negative effects on quality of everyday life. According to the literature, an 8- to 12-week program of adapted physical activity during pregnancy has proven its efficacy in treatment of low-back pain and functional disability. Stretching Postural is a nondynamic technique using muscular contractions and stretches that act mainly on the back and that can be practiced alone. OBJECTIVE: This study aimed to assess the effect of an 8-week program of standardized Stretching Postural postures in low-risk pregnant women suffering from low-back pain. STUDY DESIGN: This was an open-label, randomized, controlled trial in 1 French university hospital. Women with a singleton low-risk pregnancy between 15 and 32 weeks of gestation and with back, lumbar, or sacroiliac pain were randomly assigned (1:1) to either undergo an 8-week program of standardized Stretching Postural with basic advice (intervention group) or to receive basic advice only (control group). Both groups received ergonomic advice and encouragement to practice physical activity. The primary endpoint was the pain assessment at 8 weeks (defined by the mean pain level estimated by women in the previous week, scored on a numeric scale from 0 to 10). Secondary endpoints were pain after 4 weeks of follow-up, quality of life (12-item Short Form Survey), satisfaction (Patient Global Impression of Change), and delivery outcomes. The main analysis was intention-to-treat. RESULTS: From January 2019 to August 2020, 60 women were randomized: 30 were assigned to the intervention group and 30 to the control group. The mean level of pain at 8 weeks was significantly lower in the intervention group than in the control group (1.6±1.4 vs 4.1±2.2; P<.01). The mean 12-item Short Form Survey scores were significantly higher in the posture group than in the control group (Physical Component Score, 45.7±7.8 vs 37.4±8.5; P<.01; Mental Component Score, 54.3±5.8 vs 50.4±7.1; P=.04), and the Patient Global Impression of Change score was also significantly higher (6.1±1.5 vs 3.9±2.3; P<.01). No adverse effects were found. CONCLUSION: Stretching Postural appears to be a safe and efficient nondrug therapy to treat low-back pain during low-risk pregnancy.

A global catalog of whole-genome diversity from 233 primate species.

The rich diversity of morphology and behavior displayed across primate species provides an informative context in which to study the impact of genomic diversity on fundamental biological processes. Analysis of that diversity provides insight into long-standing questions in evolutionary and conservation biology and is urgent given severe threats these species are facing. Here, we present high-coverage whole-genome data from 233 primate species representing 86% of genera and all 16 families. This dataset was used, together with fossil calibration, to create a nuclear DNA phylogeny and to reassess evolutionary divergence times among primate clades. We found within-species genetic diversity across families and geographic regions to be associated with climate and sociality, but not with extinction risk. Furthermore, mutation rates differ across species, potentially influenced by effective population sizes. Lastly, we identified extensive recurrence of missense mutations previously thought to be human specific. This study will open a wide range of research avenues for future primate genomic research.

The landscape of tolerated genetic variation in humans and primates.

Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.

The landscape of tolerated genetic variation in humans and primates.

Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole genome sequencing data for 809 individuals from 233 primate species, and identified 4.3 million common protein-altering variants with orthologs in human. We show that these variants can be inferred to have non-deleterious effects in human based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases. One Sentence Summary: Deep learning classifier trained on 4.3 million common primate missense variants predicts variant pathogenicity in humans.

Impact of cardiac surgical timing on the neurodevelopmental outcomes of newborns with Complex congenital heart disease (CHD).

Background: More than half of infants with complex congenital heart disease (CHD) will have a neurodevelopmental disorder of multifactorial causes. The preoperative period represents a time-window during which neonates with complex CHD are in a state of hypoxia and hemodynamic instability, which fosters the emergence of brain injuries and, thus, affects early brain networks and neurodevelopmental outcomes. Currently, there is no consensus regarding the optimal age for cardiac surgery in terms of neurodevelopmental outcomes, and its definition is a real challenge. Our aim is to determine the relationship between cardiac surgical timing and long-term neurodevelopmental outcomes for various types of complex CHD. Methods: We hypothesize that earlier surgical timing could represent a neuroprotective strategy that reduces perioperative white matter injuries (WMIs) and postoperative morbidity, leading to improved neurodevelopmental outcomes in infants with complex CHD. Firstly, our prospective study will allow us to determine the correlation between age at the time of surgery (days of life) and neurodevelopmental outcomes at 24 months. We will then analyze the correlation between age at surgery and (i) the incidence of WMIs (through pre- and postoperative MRIs), (ii) postoperative morbidity, and (iii) the duration of the hospital stay. Implications and Dissemination: This research protocol was registered in the Clinical Trial Registry (National Clinical Trial: NCT04733378). This project aims to help launch the first Neurocardiac Investigation Clinic in Marseille - AP-HM - to propose an overall personalized monitoring and treatment program for patients operated on for complex CHD.

Chorionicity and neurodevelopmental outcomes at 5½ years among twins born preterm: the EPIPAGE2 cohort study.

OBJECTIVE: To compare the neurodevelopmental outcomes of preterm twins at 5½ years by chorionicity of pregnancy. DESIGN: Prospective nationwide population-based EPIPAGE2 (Etude Epidémiologique sur les Petits Âges Gestationnels) cohort study. SETTING: A total of 546 maternity units in France, between March and December 2011. POPULATION: A total of 1126 twins eligible for follow-up at 5½ years. METHODS: The association of chorionicity with outcomes was analysed using multivariate regression models. MAIN OUTCOME MEASURES: Survival at 5½ years with or without neurodevelopmental disabilities (comprising cerebral palsy, visual, hearing, cognitive deficiency, behavioural difficulties or developmental coordination disorders) were described and compared by chorionicity. RESULTS: Among the 1126 twins eligible for follow-up at 5½ years, 926 (82.2%) could be evaluated: 228 monochorionic (MC) and 698 dichorionic (DC). Based on chronicity and gestational age of birth, we found no significant differences for severe neonatal morbidity. The rates of moderate/severe neurobehavioral disabilities were similar in infants from DC pregnancies versus infants from MC pregnancies (OR 1.22, 95% CI 0.65-2.28). By gestational age and without twin-twin transfusion syndrome (TTTS), no difference according to chorionicity was found for all neurodevelopmental outcome measures. CONCLUSIONS: The neurodevelopmental outcomes among preterm twins at 5½ years is similar, irrespective of chorionicity.

Does a physiology-based interpretation of cardiotocography allow to dispense with second-line methods? A cross-sectional online survey.

CONTEXT: Second line methods are used to help obstetricians to identify abnormalities that reflect foetal acidosis. Since the use of a new technique of cardiotocography (CTG) interpretation based on the pathophysiology of the foetal period, the use of second-line tests has been questioned. OBJECTIVE: To evaluate the impact of specific training in CTG physiology-based interpretation on professional attitudes towards the use of second-line methods. METHODS: This cross-sectional study included 57 French obstetricians divided into two groups: the trained group (obstetricians who had already participated in a training course in physiology-based interpretation of CTG) and the control group. Ten medical records of patients who had abnormal CTG tracings and underwent foetal blood sampling pH measurement during labour were presented to the participants. They were given three choices: use a second-line method, continue labour without using second-line method, or perform a caesarean section. The main outcome measures was the median number of decisions to use second-line method. RESULTS: Forty participants were included in the trained group and 17 in the control group. The median number of recourses to second-line method was significantly inferior for the trained group (4/10 s-line methods) than for the control group (6/10, p = 0.040). Regarding the 4 records for which a caesarean section was the real outcome, the median number of decisions of continuing labour was significantly superior in the trained group than in the control group (p = 0.032). CONCLUSIONS: Participation in a training course in physiology-based interpretation of CTG could be associated with a less frequent use of second-line method at the cost of more frequently continuing labour with the risk compromising foetal and maternal well-being. Additional studies are required to determine whether this change in attitude is safe for the foetal well-being.

Role of magnetic resonance imaging for preoperative prediction of early biochemical failure in localized prostate cancer.

Background: The purpose of our study was to assess preoperative clinical biological and Magnetic Resonance Imaging (MRI) predictive factors of early biochemical failure (BF), defined as persistence of significant post-operative plasmatic prostate specific antigen (PSA) level after radical prostatectomy (RP) in patients with localized prostate cancer (PCa). Methods: In a retrospective cohort study we included 142 patients from our university hospital with newly diagnosed PCa, who underwent 3T multiparametric MRI prior to RP. Only the MRI target lesions [Prostate Imaging Reporting and Data System (PIRADS) ≥3] with histological correspondence were considered significant. Clinical, biological, MRI and pathological preoperative data were studied. We performed univariate and multivariate logistic regression analysis to identify significant parameters associated with early BF. Results: Early BF occurred in 14% of patients (20/142). Patients with BF had higher PSA level at diagnosis, Gleason score, number of positive biopsies, size of the largest positive biopsy and higher National Comprehensive Cancer Network (NCCN) risk score (P<0.001 for all). According to MRI, they also had higher T stage and a higher size of capsular contact (P<0.001 for all). In contrast, there was no difference concerning neither ADC value, perfusion profile and zonal location of the index lesion. In multivariate analysis, the best combination of predictive factors of early BF was the association of preoperative Gleason score ≥4+3 [odds ratio (OR) =6.8 (1.4-32.5); P=0.002] and T stage ≥3 on preoperative MRI [OR =17.4 (3.2-94.9); P<0.001] with an area under the curve (AUC) of 0.89 [99% confidence interval (CI): 0.77-1], a negative predictive value of 94% and a positive predictive value of 75%. Conclusions: Combination of simple preoperative biomarkers as Gleason score and T stage according to MRI accurately stratify the risk of early BF following RP. These results emphasize the pivotal role of preoperative MRI for the management of localized PCa.

Elevated Baseline Neutrophil Count Correlates with Worse Outcomes in Patients with Muscle-Invasive Bladder Cancer Treated with Chemoradiation.

BACKGROUND: The role of inflammation in the development and prognosis of bladder cancer (BC) is now established. We evaluated the significance of neutrophil-to-lymphocyte ratio (NLR) and neutrophil count (PNN) in patients with localized BC treated with chemoradiation. METHODS: Clinical characteristics and baseline biological data were retrospectively collected. We tested the association between NLR, PNN, and overall survival (OS) and progression-free survival (PFS). RESULTS: One hundred and ninety-four patients were included. Median PNN was 4000.0/mm3 [1500.0-16,858.0] and median NLR was 2.6 [0.6-19.2]. In patients with NLR > 2.6, median OS and PFS were lower (OS: 25.5 vs. 58.4 months, p = 0.02; PFS: 14.1 vs. 26.7 months, p = 0.07). Patients with PNN > 4000/mm3 had significantly lower OS (21.8 vs. 70.1 months, p < 0.001) and PFS (13.7 vs. 38.8 months, p < 0.001). Contrary to NLR, PNN > 4000/mm3 was associated with shorter OS and PFS in multivariate analysis. CONCLUSIONS: Elevated PNN at baseline was associated with worse OS and PFS. NLR was not an independent prognostic factor.

Relevance of Fetal Brain Magnetic Resonance Imaging Compared to Ultrasound for Detecting Cerebral Anomalies in Fetuses with Cleft Lip and/or Palate: A Cohort Study.

INTRODUCTION: Relevance of fetal brain magnetic resonance imaging (MRI) in cases of cleft lip and/or palate (CL/P) is still discussed to date. The aim of our study was to review the contribution of fetal brain MRI for detecting cerebral anomalies in cases of CL/P comparing antenatal data with neonatal outcomes. METHODS: A retrospective multicenter study was conducted from January 2010 to October 2020 in two multidisciplinary prenatal diagnosis centers among women with a fetal ultrasound (US) diagnosis of CL/P. Prenatal imaging and genetic analysis data were collected, as well as postnatal data, including outcomes of children who had an abnormal prenatal MRI. RESULTS: Among the 202 fetuses with a US diagnosis of CL/P, 96 underwent US and fetal brain MRI. 19 brain MRIs were found to be abnormal: 14 (73.7%) involved CL/P associated with other US abnormalities and five (26.3%) involved isolated clefts, of which four were cleft lip and alveolus and secondary palate (CLP). MRI identified severe abnormalities that changed the prognoses of 3 cases of clefts associated with other US abnormalities. In contrast, MRI found only minor abnormalities for the five isolated clefts, with no postnatal disorders found in these children. CONCLUSION: Fetal brain MRI should be proposed in cases of clefts associated with other anomalies or if US examination is limited by local conditions. MRI could also be discussed in cases of isolated CLP but should not be performed in cases of isolated cleft lip.

Risk factors for early occurrence of malnutrition in infants with severe congenital heart disease.

To identify the risk factors of early occurrence of malnutrition in infants with severe congenital heart disease (CHD) during their first year of life. Retrospective longitudinal multicenter study carried out from January 2014 to December 2020 in two tertiary care CHD centers. Four CHD hemodynamic groups were identified. Malnutrition was defined by a Waterlow score under 80% and/or underweight under -2 standard deviations. A total of 216 infants with a severe CHD, e.g., requiring cardiac surgery, cardiac catheterization, or hospitalization for heart failure during their first year of life, were included in the study. Malnutrition was observed among 43% of the cohort, with the highest prevalence in infants with increased pulmonary blood flow (71%) compared to the other hemodynamic groups (p < 0.001). In multivariate analysis, low birthweight (OR 0.62, 95% CI 0.44-0.89, p = 0.009), CHD with increased pulmonary blood flow (OR 4.80, 95% CI 1.42-16.20, p = 0.08), heart failure (OR 9.26, 95% CI 4.04-21.25, p < 0.001), and the number of hospitalizations (OR 1.35, 95% CI 1.08 l-1.69, p = 0.009) during the first year of life were associated with malnutrition (AUC 0.85, 95% CI 0.79-0.90).  Conclusions: In infants with a severe CHD, early occurrence of malnutrition during the first year of life affected a high proportion of subjects. CHD with increased pulmonary blood flow, low birthweight, heart failure, and repeated hospitalizations were risk factors for malnutrition. Further studies are required to identify optimal nutritional support in this population. What is Known: • Malnutrition is a known morbidity and mortality factor in children with severe congenital heart disease. What is New: • Early occurrence of malnutrition during the first year of life in infant severe congenital heart disease (CHD) was high (43%). • CHD with increased pulmonary blood flow, low birthweight, heart failure, and repeated hospitalizations during the first year of life were risk factors for malnutrition.

Adherence to oral anti-cancer therapies in older patients is similar to that of younger patients.

INTRODUCTION: The use of oral anti-cancer therapies is becoming increasingly common in the management of cancers, raising the question of adherence. The objective of this study was to assess adherence to oral anti-cancer therapies, as well as the impact of various factors that may influence it. METHODS: Patients starting oral chemotherapy (tyrosine kinase inhibitor or cytotoxic) were followed up for 3 months using a medication diary, which was given to the patient by the pharmacist during a multidisciplinary consultation. Adherence was assessed using the diary, as well as by counting the tablets they brought back. RESULTS: One hundred and fifty patients were included in the study. The main oral chemotherapy agents prescribed were palbociclib (23.3%), everolimus (18.7%), and capecitabine (13.3%). The adherence at the end of the 3 months, by means of dose intensity (i.e. percent of the dose prescribed that has been taken), was 95.5%. No significant difference in adherence was found based on age, sex, family circumstances, health status, co-medication, type of oral therapy, tumor location, number of previous treatment lines, or presence of toxicity. The main reasons for non-adherence were forgetting (50%) and toxicity (21%). Fifty-seven patients prematurely discontinued the study: 40.3% for toxicity and 36.8% for disease progression. CONCLUSION: Adherence in this study is high in comparison to literature, which can be explained by close multidisciplinary follow-up. Moreover, no significant difference was observed between younger and older patients.