Enzalutamide Reduces Oxycodone Exposure in Men with Prostate Cancer.

BACKGROUND AND OBJECTIVE: Up to 90% of patients with castration-resistant prostate cancer (CRPC) will develop symptomatic bone metastases requiring pain medication, with opioids being the mainstay of therapy in treating moderate and severe pain. Enzalutamide is an androgen receptor antagonist for the treatment of CRPC and a strong inducer of cytochrome P450 (CYP)3A4. Hereby, enzalutamide potentially reduces the exposure of oxycodone, an opioid metabolized by CYP3A4 and CYP2D6. Our objective was to evaluate the potential drug-drug interaction of enzalutamide and oxycodone. METHODS: A prospective, nonrandomized, open-label, two-arm parallel study was performed. All patients received a single dose of 15 mg normal-release oxycodone. Patients in the enzalutamide arm (ENZ-arm) received enzalutamide 160 mg once daily. Plasma concentrations of oxycodone and its metabolites were quantified using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. RESULTS: Twenty-six patients (13 ENZ-arm; 13 control arm) were enrolled in the study. Enzalutamide decreased the mean AUC0-8 h and Cmax of oxycodone with, respectively, 44.7% (p < 0.001) and 35.5% (p = 0.004) compared with the control arm. The AUC0-8 h and Cmax of the active metabolite oxymorphone were 74.2% (p < 0.001) and 56.0% (p = 0.001) lower in the ENZ-arm compared with the control arm. In contrast, AUC0-8 h and Cmax of the inactive metabolites noroxycodone and noroxymorphone were significantly increased by enzalutamide. CONCLUSION: Co-administration of enzalutamide significantly reduced exposure to oxycodone and its active metabolite oxymorphone in men with prostate cancer. This should be taken into account when prescribing enzalutamide combined with oxycodone.

[Toxoplasmosis in pregnancy: Practical Management]. / Toxoplasmose pendant la grossesse : proposition actuelle de prise en charge pratique.

The burden of congenital toxoplasmosis has become small in France today, in particular as a result of timely therapy for pregnant women, fetuses and newborns. Thus, the French screening and prevention program has been evaluated and recently confirmed despite a decline over time in the incidence of toxoplasmosis. Serological diagnosis of maternal seroconversion is usually simple but can be difficult when the first trimester test shows the presence of IgM, requiring referral to an expert laboratory. Woman with confirmed seroconversion should be referred quickly to an expert center, which will decide with her on treatment and antenatal diagnosis. Although the level of proof is moderate, there is a body of evidence in favor of active prophylactic prenatal treatment started as early as possible (ideally within 3 weeks of seroconversion) to reduce the risk of maternal-fetal transmission, as well as symptoms in children. The recommended therapies to prevent maternal-fetal transmission are: (1) spiramycin in case of maternal infection before 14 gestational weeks; (2) pyrimethamine and sulfadiazine (P-S) with folinic acid in case of maternal infection at 14 WG or more. Amniocentesis is recommended to guide prenatal and neonatal care. If fetal infection is diagnosed by PCR on amniotic fluid, therapy with P-S should be initiated as early as possible or continued in order reduce the risk of damage to the brain or eyes. Further research is required to validate new approaches to preventing congenital toxoplasmosis.

Prenatal stomach position predicts gastrointestinal morbidity at 2 years in fetuses with left-sided congenital diaphragmatic hernia.

OBJECTIVE: The long-term morbidity associated with isolated left-sided congenital diaphragmatic hernia (CDH) has been described previously. However, antenatal criteria impacting gastrointestinal morbidity (GIM) are not yet defined. The objective of this study was to evaluate the effect of fetal stomach position on the risk of GIM at 2 years of age in children with left-sided CDH. METHODS: This was a retrospective, observational multicenter cohort study of data obtained from January 2010 to January 2014, that included patients whose fetus had isolated left-sided CDH, with or without fetal endoscopic tracheal occlusion (FETO). Prenatal maternal, fetal and pediatric data were collected. Fetal stomach position was evaluated a posteriori by two observers, using ultrasound images at the level of the four-chamber view of the heart that had been obtained to calculate the observed-to-expected lung-area-to-head-circumference ratio (O/E-LHR). Fetal stomach position was graded as follows: Grade 1, stomach not visualized; Grade 2, stomach visualized anteriorly, next to the apex of the heart, with no structure in between the stomach and the sternum; Grade 3, stomach visualized alongside the left ventricle of the heart, and abdominal structures anteriorly; or Grade 4, as Grade 3 but with stomach posterior to the level of the atrioventricular heart valves. The primary outcome was GIM at 2 years of age, assessed in a composite manner, including the occurrence of gastroesophageal reflux disease, need for gastrostomy, duration of parenteral and enteral nutrition and persistence of oral aversion. Regression analysis was performed in order to investigate the effect of O/E-LHR, stomach position and FETO on various GIM outcome variables. RESULTS: Forty-seven patients with fetal left-sided CDH were included in the analysis. Thirteen (27.7%) infants did not meet the criterion of exclusive oral feeding at 2 years of age. Fetal stomach position grade was associated significantly and independently with the duration of parenteral nutrition (odds ratio (OR), 19.86; P = 0.031) and persistence of oral aversion at 2 years (OR, 3.40; P = 0.006). On multivariate analysis, O/E-LHR was predictive of the need for prosthetic patch repair, but not for GIM. FETO did not seem to affect the risk of GIM at 2 years. CONCLUSION: In isolated left-sided CDH, fetal stomach position is the only factor that is predictive of GIM at 2 years of age. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

[Induced abortions for maternal indications: Retrospective study in Western Normandy between 2010 and 2019]. / Interruptions médicales de grossesse pour indications maternelles : analyse rétrospective en Normandie Occidentale (2010­2019).

INTRODUCTION: Termination of pregnancy for maternal reasons (MTOP) are authorized in France without limit of term when "the continuation of the pregnancy puts in serious danger the health of the woman". The literature on the subject is rare and we wanted to make an inventory in our region. METHODS: Retrospective observational study between 2010 and 2019 at the multidisciplinary center for prenatal diagnosis in Western Normandy. RESULTS: Thirty-one cases of MTOP were included (2.5% of all TOP). At the CHU de Caen, they represented one in 1200 births. Twenty-three percent of MTOP had a psychosocial or psychiatric indication (average term=22 SA) and 29% an obstetric indication due to severe preeclampsia (23 SA). Finally, 48% were linked to a non-obstetric somatic disorder including 46% pre-existing pathologies (average term=11 SA), most often cardiological or nephrological and 54% diagnosed during pregnancy (17 SA) dominated by neoplasias. They were more often (68%) performed in the second trimester. Vaginal births were more frequent (74% against 26% of endouterine aspirations). CONCLUSION: Strict medical contraindications to pregnancy are exceptional. Recourse to the medical termination of pregnancy within the framework of a preexisting pathology must remain rare, by systematizing of the preconception consultation.

Drug-induced enterocolitis syndrome (DIES) in a 10-year-old girl.

We report the case of a child presenting with an adverse drug reaction highly suggestive of drug-induced enterocolitis syndrome (DIES) to amoxicillin (AMX). A 10-year-old girl developed repetitive vomiting and pallor without cutaneous or respiratory symptoms 2h after AMX intake. DIES is not a well-described entity, and very few data are available in the literature. In the absence of an existing definition, the diagnosis of DIES can only be suspected and is based on its homology with food protein-induced enterocolitis (FPIES). The major criterion is the recurrence of repetitive and often incoercible vomiting occurring within 1-4h of ingestion of the culprit food in the absence of IgE-mediated allergic classic skin and respiratory symptoms. Once the diagnosis of DIES to AMX is suspected, an open challenge with AMX should be undertaken with caution, under medical supervision in a day hospital unit because of the risk of severe recurrence. Once the diagnosis is confirmed, AMX should be contraindicated to avoid severe reactions.

Iatrogenic mediastinitis in bronchiolitis: Importance of avoiding pharyngeal aspiration.

An 11-month-old infant was hospitalized for his first episode of severe bronchiolitis, with pneumomediastinum on the chest x-ray performed in the emergency room before hospitalization. After a few days, the occurrence of a feverish torticollis motivated a CT scan, revealing mediastinitis. An iatrogenic perforation was objectified in the posterior wall of the esophagus, probably caused by nasopharyngeal aspiration. This exceptional case has never been reported before, except in premature infants. This encouraged us to report this case to change systematic aspiration practices and prefer nasal suctioning in healthy infants with bronchiolitis presenting to the emergency department.

[Prospective evaluation of the knowledge of couples concerning the prenatal screening ultrasound]. / Évaluation prospective des connaissances des couples concernant l'échographie de dépistage prénatal.

OBJECTIVES: Evaluation of the knowledge of couples concerning the prenatal screening ultrasound in order to improve information. METHODS: This prospective, observational and comparative study was carried out in three maternal centers: a level III maternity, a level II private maternity, and a private gynecologist's office where prenatal screening ultrasounds were performed between the first of March 2018 and the 31th of April 2018. A questionnaire was given to all pregnant women coming to consult for a prenatal screening ultrasound. It included items on maternal characteristics, pregnancy characteristics, and screening ultrasound. RESULTS: One hundred and sixty-nine women answered the questionnaire. On the 138 participants who had consulted in the level III maternity, 42 % expected them to study fetal well-being, 38 % growth, and 13 % malformation. Forty-six percent attested to have received a request for consent, as well as information about these ultrasounds. The same is true for the 120 spouses in thelevel III maternity where only 7 % expected a malformation search to be carried out. The number of participants in the type II private maternity and the private gynecologist's office was insufficient. CONCLUSION: The information given and received, and the knowledge of couples in this level III maternity about the prenatal screening ultrasound seem to be insufficient. It is therefore important to inform the pregnant women and their spouse by giving consent before the first ultrasound and by a verbal message, simple and clear about what the professional is looking for in order to reduce this discrepancy, and thus prepare the couple in case of announcement of an anomaly.

Prenatally diagnosed periventricular nodular heterotopia: Further delineation of the imaging phenotype and outcome.

OBJECTIVES: Periventricular nodular heterotopia (PNH) is a malformation of cortical development which presents with heterogeneous imaging, neurological phenotype and outcome. There is a paucity of comprehensive description detailing the prenatal diagnosis of PNH. The aim of this study is to report neuroimaging features and correlated outcomes in order to delineate the spectrum of prenatally diagnosed PNH. METHODS: It was a retrospective study over 15 years in five tertiary centers. All fetuses with prenatally diagnosed PNH were collected. Fetal ultrasound and MRI were reviewed and genetic screening collected. Prenatal findings were analyzed in correlation to fetopathological analyses and post-natal follow up. RESULTS: Thirty fetuses (22 females and 8 males) with PNH were identified. The two major ultrasound signs were ventriculomegaly associated with dysmorphic frontal horns (60%) and posterior fossa anomalies (73.3%). On MRI, two groups of PNH were identified: the contiguous and diffuse PNH (n = 15, 50%), often associated with megacisterna magna, and the non-diffuse, either anterior, posterior or unilateral PNH. FLNA mutations were found in 6/11 cases with diffuse PNH. Additional cortical malformations were exclusively observed in non diffuse PNH (9/15; 60%). Twenty-four pregnancies (80%) were terminated. Six children aged 6 months to 5 years are alive. Five have normal neurodevelopment (all had diffuse PNH) whereas one case with non diffuse PNH has developmental delay and epilepsy. CONCLUSION: PNH is heterogeneous but patients with diffuse PNH are a common subgroup with specific findings on prenatal imaging and implications for prenatal counseling.

[Uterine rupture of the unscarred uterus: A report of 10 cases]. / Rupture utérine sur utérus non cicatriciel : à propos de 10 cas.

INTRODUCTION: Uterine rupture in the healthy uterus is a rare obstetrical complication, not much suspected and with badly identified risk factors. Thus, there exists frequent delay for treatment and therefore fetal-maternal important morbidity and mortality. This article describes clinical signs and symptoms, management, and maternal and neonatal prognosis of uterine rupture. METHODS: Descriptive retrospective study within 13 maternity hospitals, reporting 10 series of cases of uterine rupture on gravid healthy uterus during the third trimester of pregnancy. RESULT: The incidence was 2.8/100,000 births. Surgical treatment was conservative in 9 out of 10 cases, the maternal prognosis was good with no maternal deaths and 6 out of 7 patients had at least one subsequent pregnancy. The fetal prognosis was more reserved, with 2 fetal or neonatal deaths and 1 with motor disability. 6/6 patients (100%) had at least one iterative Caesarean section during the following pregnancies with healthy fetuses. CONCLUSION: In this series of 10 cases over 25years, maternal-fetal morbidity and mortality were significant, in agreement with the literature. Maternal prognosis remained favorable. When surgical treatment is conservative a subsequent pregnancy is possible and an iterative cesarean section must be performed.

Potentially preventable tuberculosis cases in children exposed to a contaminant case.

Early screening is recommended in children exposed to a contagious case of tuberculosis (TB), to prevent rapid progression to active TB. The aim of this study was to evaluate the percentage of potentially preventable cases of pediatric TB stemming from inadequate screening. The data gathered on children aged 0 to 10 years, who were evaluated by the Paris Center for TB Control (CLAT75) between January 2009 and December 2013, were extracted and retrospectively analyzed. French National Guidelines for screening were used as reference. During the study period, 1232 children 0-10 years were screened, because of a known exposure to an index case, including 124 (10%) with criteria for latent tuberculosis infection (LTBI) and 26 (2%) with active TB. Twelve additional cases of TB were reported, diagnosed based on symptoms or systematic exams. As a whole, 68% of pediatric TB cases were diagnosed at screening around an adult index case, highlighting the quality of the screening network. Among the 38 TB cases, 19 (50%) had a missed opportunity for potential prevention, due to the absence of screening despite a known contaminant (n=2) or to screening not in compliance with current recommendations (n=17). Delayed first evaluation was the most frequent error of the screening procedures. In conclusion, despite the quality of the screening network set up in Paris, half of the pediatric TB cases in this study did not undergo the recommended screening procedures. A significant reduction in the number of pediatric TB cases can be expected through the optimization of screening networks.

Rate of caesarean sections according to the Robson classification: Analysis in a French perinatal network - Interest and limitations of the French medico-administrative data (PMSI).

INTRODUCTION: The objective of our study was to determine, in accordance with WHO recommendations, the rates of Caesarean sections in a French perinatal network according to the Robson classification and determine the benefit of the medico-administrative data (PMSI) to collect this indicator. This study aimed to identify the main groups contributing to local variations in the rates of Caesarean sections. MATERIAL AND METHODS: A descriptive multicentric study was conducted in 13 maternity units of a French perinatal network. The rates of Caesarean sections and the contribution of each group of the Robson classification were calculated for all Caesarean sections performed in 2014. The agreement of the classification of Caesarean sections according to Robson using medico-administrative data and data collected in the patient records was measured by the Kappa index. We also analysed a 6 groups simplified Robson classification only using data from PMSI, which do not inform about parity and onset of labour. RESULTS: The rate of Caesarean sections was 19% (14.5-33.2) in 2014 (2924 out of 15413 deliveries). The most important contributors to the total rates were groups 1, 2 and 5, representing respectively 14.3%, 16.7% and 32.1% of the Caesarean sections. The rates were significantly different in level 1, 2b and 3 maternity units in groups 1 to 4, level 2a maternity units in group 5, and level 3 maternity units in groups 6 and 7. The agreement between the simplified Robson classification produced using the medical records and the medico-administrative data was excellent, with a Kappa index of 0.985 (0.980-0.990). CONCLUSION: To reduce the rates of Caesarean sections, audits should be conducted on groups 1, 2 and 5 and local protocols developed. Simply by collecting the parity data, the excellent metrological quality of the medico-administrative data would allow systematisation of the Robson classification for each hospital.

In-utero aspiration vs expectant management of anechoic fetal ovarian cysts: open randomized controlled trial.

OBJECTIVE: To assess the efficacy and safety of in-utero aspiration (IUA) of anechoic fetal ovarian cysts. METHODS: This multicenter, prospective, randomized open trial in two parallel groups included women from nine outpatient fetal medicine departments with singleton pregnancy ≥ 28 weeks of gestation and a female fetus with an ultrasound-diagnosed simple ovarian cyst, defined as a single fully anechoic cystic structure measuring ≥ 30 mm. They were allocated randomly to IUA under ultrasound guidance or expectant management. All procedures were performed by trained senior obstetricians. Primary outcome was need for neonatal intervention, by laparoscopy, laparotomy or transabdominal aspiration. Secondary outcomes were in-utero involution of the cyst and oophorectomy at birth. Analyses were conducted according to the intention-to-treat principle. RESULTS: Of 61 participants, 34 were allocated to IUA and 27 to expectant management. Three IUA procedures (9%) could not be performed (one due to fetal position and two due to aspirations being dry). The remaining 31 IUA procedures were uneventful. The incidence of neonatal intervention did not differ significantly between the IUA and the expectant management groups (20.6% vs 37.0%; relative risk (RR), 0.55; 95% CI, 0.24-1.27). Nonetheless, IUA was associated with increased incidence of in-utero involution of the cyst (47.1% vs 18.5%; RR, 2.54; 95% CI, 1.07-6.05) and reduced rate of oophorectomy (3.0% vs 22.0%; RR, 0.13; 95% CI, 0.02-1.03) compared with expectant management. CONCLUSION: IUA of anechoic fetal ovarian cysts, compared with expectant management, was not associated with a reduction in overall neonatal interventions but was associated with a reduced oophorectomy rate. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

[Hot tub lung: A case report]. / Poumon de jacuzzi : à propos d'un cas.

Hot tub lung is a type of hypersensitivity pneumonitis caused by inhalational exposure to the Mycobacterium avium complex. We report the case of a 14-year-old boy presenting dyspnea with hypoxemia, whose medical history and clinical course helped make the diagnosis. Infectious causes were considered first, and antibiotics were initiated without success. Further questioning and explorations led to discussing a hypersensitivity pneumonitis diagnosis. Relapse after exposure to a hot tub enabled us to confirm hot tub lung. Hypersensitivity pneumonitis is a rare cause of pulmonary disorder, especially in children. It should be discussed with unusually severe and progressive cough or dyspnea. Further explorations should therefore be undertaken (CT, fibroscopy). Taking a precise medical history allows early diagnosis, leading to a quick withdrawal from the allergenic source and appropriate treatments.

[Perineal groove: Case report and review of the literature]. / Rainure périnéale congénitale : à propos d'un cas.

Perineal groove is a rare anoperineal congenital malformation, usually occurring in girls, unknown to many pediatricians. We report the case of a 17-day-old girl admitted for urinary infection, who presented a wet sulcus with mucous membrane, extending from the vaginal fourchette to the anterior border of the anus. The diagnosis of perineal groove was clinically confirmed, after elimination of misdiagnosis such as infection or trauma. This benign malformation tends to be self-epithelialized in the 1st year of life, and no surgical treatment is recommended, except for cosmetic reasons or for recurrent infections. This diagnosis must be known so as to avoid unnecessary explorations and anxiogenic misdiagnosis.

[Evaluating a child after a febrile seizure: Insights on three important issues]. / Évaluation d'un enfant après une crise fébrile : focus sur trois problèmes de pratique clinique.

Febrile seizures (FS) are the most common seizures seen in the paediatric population in the out-of-hospital and emergency department settings, and they account for the majority of seizures seen in children younger than 5 years old. An FS is a seizure accompanied by fever, without central nervous system infection, occurring in children between 6 months and 5 years old. Five criteria have been used and taught to classify any FS as simple or complex FS. These factors do not bear the same significance for clinical practice, in particular, the decision to perform a lumbar puncture for cerebrospinal fluid analysis to rule out an intracranial infection. Moreover, epidemiological studies have illustrated that some factors are predictive of febrile seizure recurrence while others are predictive of epilepsy occurrence. On this basis, a workshop was organized to provide an answer to three clinical practice questions: when should a lumbar puncture be performed in a child who has experienced a seizure during a fever episode, is the prescription of a rescue drug required with a risk of a prolonged febrile seizure recurrence, when should a neurological consultation be requested (risk of later epilepsy)? Based on a review of the literature and on a 1-day workshop, we report here the conclusion of the working group. A lumbar puncture is required in any child with meningitis symptoms or septic signs or behaviour disturbance. A lumbar puncture should be discussed based on the clinical symptoms and their progression over time when a child has experienced a focal FS or repetitive FSs without signs of meningitis or sepsis or behaviour disturbance. The lumbar puncture is not necessary in case of simple FS without signs of meningitis, including in infants between 6 and 12 months old. An early clinical evaluation (at least 4 h after the first clinical assessment) could be helpful, in particular in infants younger than 12 months of age. A rescue drug might be prescribed when there is a high risk of prolonged FS (i.e., risk higher than 20%): age at FS<12months OR a history of a previous febrile status epilepticus OR if the first FS was a focal seizure OR abnormal development/neurological exam/MRI OR a family history of nonfebrile seizure. A neurological consultation should be requested for any child who has experienced a prolonged FS before the age of 1 year, for children who have experienced prolonged and focal FS or repetitive (within 24h) focal FS, for children who have experienced multiple complex (focal or prolonged or repetitive) FS, for children with an abnormal neurological exam or abnormal development experiencing a FS. Although childhood febrile seizures in most cases are benign, witnessing such seizures is always a terrifying experience for the child's parents. Most parents feel that their child is dying or could have severe brain injury related to the episode. Therefore, the group also suggests a post-FS visit with the primary care physician.

Intervention of the obstetrician during childbirth in a supposedly low-risk population and influence of parity.

OBJECTIVE: Compare obstetrician intervention and calling rates during labour and delivery between low-risk and high-risk women and study the influence of parity on these rates. MATERIAL AND METHODS: Descriptive retrospective study conducted on 227 patients in a university maternity unit (level 3 university hospital maternity unit) between 1st and 30th January 2014. The low- and high-risk populations were characterised according to the French National Authority for Health (HAS) and NICE guidelines. The obstetrician intervention criteria were: Caesarean section, instrumental vaginal delivery, artificial delivery/uterus examination and postpartum haemorrhage. The obstetrical team also had to call the obstetrician in case of foetal heart rate abnormalities, scalp blood pH measurement, third and/or fourth degree perineal tears, labour dystocia, or any other severe event occurring during labour or delivery. RESULTS: In univariate analysis, the obstetrician intervention rates were respectively 44.5% and 34.4% in the high- and low-risk groups (P=0.13). The obstetrician calling rates were similar between the two groups. Using logistic regression model including parity, the obstetrician intervention rate became significantly higher in the "high-risk" group (OR 2.044, 95% CI 1.129-3.703, P=0.018). In the low-risk population, the intervention rate was significantly increased for nulliparous women compared with multiparas (47.5% versus 9.7%, P<0.001, OR=8.2, CI 95% 2.2 to 46.9). CONCLUSION: One third of the women defined as low-risk patients appear to need an obstetrician intervention during labour and delivery, with a major influence of parity.

Practice of pathological examinations in stillbirths: A 10-year retrospective study.

OBJECTIVES: To describe the practice of fetal and placental pathological examinations in a large series of spontaneous stillbirths over 10 years. MATERIALS AND METHODS: Inclusion of cases recorded by the Lower Normandy Regional Fetal-Infant Mortality Observatory (observatoire régional de mortalité fœto-infantile) from January 1, 2005 to December 31, 2014. The possible cause of death was coded in accordance with the ReCoDe classification system. RESULTS: Seven hundred and forty-four cases were recorded. The placental examinations were conducted in 93.7% of cases (CI95%[91.7-95.3]), increasing over the study period, and an autopsy was proposed in 87.2% of cases (CI95%[84.8-89.6]). Autopsy was conducted less frequently during the most recent period, with parental refusal increasing over time. In multivariate analysis, no factor was associated with a higher frequency of placental examinations, while autopsy was proposed more often under certain circumstances: less than 4 pregnancies (P<10-2), birth weight from 1000 to 1500 grams (P=0.05), singleton (P<10-2), clinical context not suggesting a cause (P<10-3), type 1 or 2 maternity ward (P<10-2), antepartum death (P<10-3). CONCLUSION: Placental analysis was almost systematically realized, as suggested by international guidelines. Fetal autopsy was often performed, however only in some specific circumstances. New practice guidance to realize customized fetal autopsies appear to be necessary.