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OBJECTIVE: To determine the prevalence of pulmonary hypertension(PAH) in left-sided congenital diaphragmatic hernia(CDH); how we could predict it; and how PAH contributed to the model for mortality prediction.; STUDY DESIGN: Retrospective analysis in three European centers. The primary outcome was the presence of PAH on postnatal day(d)1,7, and at discharge. Studied predictors of PAH were: observed/expected-lung/head-ratio(o/e LHR), liver-herniation, FETO, and gestational age(GA) at delivery. The combined effect of pre-and postnatal variables on mortality was modeled by Cox regression.; RESULTS: Of the 197 neonates, 56(28.4%) died. At d1, 67.5%(133/197) had PAH and 61.9% (101/163) by d7. Overall, 6.4% (9/141) had PAH at discharge.At d1, o/eLHR(OR 0.96) and FETO(OR 2.99) independently correlated to PAH(AUC:0.74). At d7, PAH significantly correlated only with the use of FETO (OR 3.9;AUC:0.65). None were significant for PAH at discharge.Combining the occurrence of PAH with antenatal biomarkers improved mortality prediction(p=0.02), in a model including o/eLHR(HR:0.94), FETO(HR:0.35), liver herniation(HR:16.78), and PAH(HR:15.95).; CONCLUSIONS: Antenatal prediction of PAH was only moderate. The postnatal occurrence of PAH further increases the risk of death. Whereas this may be used to counsel parents in the postnatal period, our study demonstrates there is a need to find more accurate antenatal predictors for PAH. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

OBJECTIVES: the MOMS randomized trial has demonstrated that prenatal spina bifida aperta (SBA) repair via open approach is safe and effective for both mother and fetus, yet half of the infants have incomplete reversal of hindbrain herniation and no improvement in neuromotor function. One contributing factor may be the incompleteness of the neurosurgical repair causing persistent in utero leakage of cerebrospinal fluid (CSF) and exposure of the spinal cord to the amniotic fluid until birth. We aim to investigate the neurostructural and neurofunctional efficacy of the watertightness of prenatal SBA repair. METHODS: a superiority study was conducted in the validated SBA fetal lamb model and powered (n=7 per group). Outcomes of lambs undergoing watertight or non-watertight multilayer repairs through an open approach were compared to those in unrepaired SBA lambs at delivery (term=145 days). At ~75-day fetal lambs underwent standardized induction of lumbar SBA. At ~100 days, they were assigned to one of the three groups and subsequently to either watertight or non-watertight layered repair group based on an intraoperative watertightness test using subcutaneous fluoresceine injection. Finally, at 1-2 postnatal days, we assessed reversal of hindbrain herniation on Magnetic Resonance Imaging (MRI) as primary outcome. Secondary proxies of neuroprotection were CSF leakage at the repair site; hindlimb motor function based on joint movement score, locomotor grade and Motor Evoked Potentials (MEP); neuroprotection score encompassing live birth, hindbrain herniation reversal, absent CSF leakage and joint score =9/15; and brain and spinal cord histology and immunohistochemistry. As the watertightness test is not clinically usable, we developed a potential surrogate intraoperative quality score and assessed its relationship with improved outcomes. This four-point scoring system is based on visual assessment of the quality of the skin repair (suture inter-run distance =3mm, absence of tear and ischemia). RESULTS: Compared to unrepaired lambs, watertight repair was neuroprotective in 5/7 lambs (neuroprotection score of 4/4), as evidenced by a 100% reversal of hindbrain herniation on MRI; lower CSF leakage rate (14%); better hindlimb motor function evidenced by higher joint movement score, locomotor grade, and MEP area-under-the-curve and peak-to-peak amplitude; higher neuronal density in the hippocampus and corpus callosum; and higher reactive astrogliosis at the SBA lesion epicenter. Conversely, non-watertight SBA repair did not achieve the same level of neuroprotection (1/7) due to non-significant 86% hindbrain herniation reversal, no motor function improvement, high CSF leakage (43%), low brain neuron count in both regions and low spinal astroglial cell area at the epicenter. Like watertight layered repair, a high quality score (=2/3) was associated with improved outcomes yet watertightness test and quality score could not be used interchangeably due to results discrepancies. CONCLUSIONS: A watertight layered fetal SBA repair improves brain and spinal cord structure and function in the fetal lamb model. This translational research has important clinical implication and neurosurgical technique that achieves watertightness should be adopted in all fetal centers to improve neuroprotection. Future clinical studies could assess whether the high quality of the repair correlates with clinical outcomes for neuroprotection. This article is protected by copyright. All rights reserved.

Congenital diaphragmatic hernia can be diagnosed in the prenatal period and its severity can be measured by fetal imaging. There is now level I evidence that, in selected cases, Fetoscopic Endoluminal Tracheal Occlusion with a balloon increases survival to discharge from the neonatal unit as well as the risk for prematurity. Both effects are dependent on the time point of tracheal occlusion. Fetoscopic Endoluminal Tracheal Occlusion may also lead to iatrogenic death when the balloon cannot be timely retrieved. The implementation of the findings from our clinical studies, may also vary based on local conditions. These may be different in terms of available skill set, access to fetal therapy, as well as outcome based on local neonatal management. We encourage prior benchmarking of local outcomes with optimal postnatal management, based on large enough numbers and using identical criteria as in the recent trials. We propose to work further on prenatal prediction methods, and the improvement of fetal intervention. In this manuscript, we describe a research agenda from a fetal medicine perspective. This research should be in parallel with innovation in neonatal and pediatric (surgical) management of this condition.

Fetal growth restriction (FGR) in human pregnancy is associated with perinatal mortality, short- and long-term morbidities. No prenatal therapy is currently established despite decades of research. We aimed to review interventions in animal models for prenatal FGR treatment, and to seek the next steps for an effective clinical therapy. We registered our protocol and searched MEDLINE, Embase, and The Cochrane Library with no language restrictions, in accordance with the PRISMA guideline. We included all studies that reported the effects of any prenatal intervention in animal models of induced FGR. From 3257 screened studies, 202 describing 237 interventions were included for the final synthesis. Mice and rats were the most used animals (79%) followed by sheep (16%). Antioxidants (23%), followed by vasodilators (18%), nutrients (14%), and immunomodulators (12%) were the most tested therapy. Two-thirds of studies only reported delivery or immediate neonatal outcomes. Adverse effects were rarely reported (11%). Most studies (73%), independent of the intervention, showed a benefit in fetal survival or birthweight. The risk of bias was high, mostly due to the lack of randomization, allocation concealment, and blinding. Future research should aim to describe both short- and long-term outcomes across various organ systems in well-characterized models. Further efforts must be made to reduce selection, performance, and detection bias.

Objective To assess the safety of Partial-Amniotic-Insufflation-of-heated-humidified-CO2 (hPACI) during fetoscopic spina bifida repair (fSB-repair). Method A simulated fSB-repair through an exteriorized uterus under hPACI was performed in 100-day fetal lambs (term = 145 days) under a laboratory anesthesia protocol (n = 5; group 1) which is known to induce maternal-fetal acidosis and hypercapnia. Since these may not occur clinically, we applied a clinical anesthesia protocol (n = 5; group 2), keeping maternal parameters within physiological conditions, that is, controlled maternal arterial carbon dioxide (CO2) pressure (pCO(2) = 30 mmHg), blood pressure (>= 67 mmHg), and temperature (37.1-39.8 degrees C). Our superiority study used fetal pH as the primary outcome. Results Compared to group 1, controlled anesthesia normalized fetal pH (7.23 +/- 0.02 vs. 7.36 +/- 0.02, p < 0.001), pCO(2) (70.0 +/- 9.1 vs. 43.0 +/- 1.0 mmHg, p = 0.011) and bicarbonate (27.8 +/- 1.1 vs. 24.0 +/- 0.9 mmol/L, p = 0.071) at baseline. It kept them within clinically acceptable limits (pH >= 7.23, pCO(2) = 120 min of hPACI as opposed to

Congenital Diaphragmatic Hernia (CDH) is a rare congenital anomaly characterized by a defect in the diaphragm, which permits abdominal organs to herniate into the thorax. This causes lung hypoplasia and at birth, children with CDH experience respiratory distress and pulmonary hypertension. Despite optimal neonatal treatment, CDH is still associated with a high mortality and morbidity. In severe cases, Fetal Intervention (FETO) may alter the natural course of this disease. Herein we describe the rationale, action mechanism and technique to perform this intervention. Despite hope giving results, this technique remains investigational for left sided CDH. However, an increased survival may come at the cost of increased morbidity. Children born with CDH are at increased risk for long and short-term morbidity, including neurodevelopmental problems. Until now, there are still uncertainties about the severity and prevalence of neurologic morbidity. Furthermore, it remains uncertain if these problems are already present prenatally and if a prenatal intervention influence this.

Objective: To compare the host and biomechanical response to a fully absorbable poly-4-hydroxybutyrate (P4HB) scaffold to the response to PP mesh in an animal model of vaginal POP surgery. Design: A study employing a sheep model Setting: KU Leuven Center for Surgical Technologies Population: 14 parous female Mule sheep Methods: P4HB scaffolds were surgically implanted in the posterior vaginal wall of sheep. The comparative PP mesh data were obtained from an identical protocol. Main outcome measures: Gross necropsy, histological and biomechanical evaluation of explants, and the in vivo P4HB scaffold degradation were evaluated at 60- and 180-days post-implantation. Results: Gross necropsy revealed no implant related adverse events using P4HB scaffolds. The tensile stiffness of the P4HB explants increased at 180-days (12.498 ± 2.66 N/mm (P=0.019)) as compared to 60-days (4.585 ± 1.57 N/mm) post-implantation, while P4HB degraded gradually. P4HB scaffolds exhibited excellent tissue integration with dense connective tissue and a moderate initial host response. P4HB scaffolds induced a significantly higher M2/M1 ratio (1.70 ± 0.67 SD, score 0-4), as compared to PP mesh (0.99 ± 0.78 SEM, score 0-4) at 180-days. Conclusions: P4HB scaffold facilitated a gradual load transfer to vaginal tissue over time. The fully absorbable P4HB scaffold, in comparison to PP mesh, has a favorable host response with comparable load bearing capacity. If these results are also observed at longer follow-up, a clinical study for vaginal POP surgery may be warranted to demonstrate efficacy. Key words: Pelvic organ prolapse, vaginal surgery, Poly-4-hydroxybutyrate, degradable scaffold, host response, biomechanics.

Open fetal surgery for spina bifida (SB) is safe and effective yet invasive. The growing interest in fetoscopic SB repair (fSB-repair) prompts the need for appropriate training. We aimed to develop and validate a high-fidelity training model for fSB-repair. fSB-repair was simulated in the abdominal cavity and on the stomach of adult rabbits. Laparoscopic fetal surgeons served either as novices (n = 2) or experts (n = 3) based on their experience. Technical performance was evaluated using competency Cumulative Sum (CUSUM) analysis and the group splitting method. Main outcome measure for CUSUM competency was a composite binary outcome for surgical success, i.e. watertight repair, operation time = 180 min and Objective-Structured-Assessment-of-Technical-Skills (OSATS) score = 18/25. Construct validity was first confirmed since competency levels of novices and experts during their six first cases using both methods were significantly different. Criterion validity was also established as 33 consecutive procedures were needed for novices to reach competency using learning curve CUSUM, which is a number comparable to that of clinical fSB-repair. Finally, we surveyed expert fetal surgeons worldwide to assess face and content validity. Respondents (26/49; 53%) confirmed it with = 71% of scores for overall realism = 4/7 and usefulness = 3/5. We propose to use our high-fidelity model to determine and shorten the learning curve of laparoscopic fetal surgeons and retain operative skills.

OBJECTIVE: Children with congenital diaphragmatic hernia (CDH) are at risk for neurodevelopmental delay. Herein we report on prenatal changes in biometry and brain perfusion in fetuses with isolated CDH. STUDY DESIGN: This retrospective study evaluated fetuses with isolated, left-sided CDH in three European referral centers. Abdominal circumference (AC), femur length (FL), head circumference (HC), transcerebellar diameter (TCD), middle cerebral artery (MCA) Doppler, and ventricular width (VW) were assessed during four gestational periods (33 weeks). Z-scores were calculated, and growth curves were created based on longitudinal data. RESULTS: In 367 fetuses, HC, AC and FL were within normal ranges throughout gestation. The TCD diminished with advancing gestational age to fall below the fifth percentile after 32 weeks. A less pronounced but similar trend was seen in VW. The peak systolic velocity of the MCA was consistently approximately 10% lower than normal. Disease severity was correlated to TCD (p = 0.002) and MCA doppler values (p = 0.002). There were no differences between fetuses treated with FETO and those managed expectantly. CONCLUSION: Fetuses with isolated left-sided CDH have a small cerebellum and reduced MCA peak systolic velocity. Follow up studies are necessary to determine the impact of these changes on neurodevelopment.

Congenital diaphragmatic hernia is characterized by failed closure of the diaphragm, thereby allowing abdominal viscera to herniate into the thoracic cavity and subsequently interfering with normal lung development. At birth, pulmonary hypoplasia leads to respiratory insufficiency and persistent pulmonary hypertension (PHT), that is lethal in up to 32% of patients. In isolated cases, the outcome may be predicted prenatally by medical imaging and advanced genetic testing. In those fetuses with a predicted poor outcome, fetoscopic endoluminal tracheal occlusion may be offered. This procedure is currently being evaluated in a global randomized clinical trial (www.TOTALtrial.eu). We are currently investigating alternative strategies including transplacental sildenafil administration to reduce the occurrence of persistent PHT.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is characterized by a defective closure of the diaphragm occurring as an isolated defect in 60% of cases. Lung size, liver herniation, and pulmonary circulation are major prognostic indices. Isolated CDH genetics is heterogeneous and poorly understood. Whether genetic lesions are also outcome determinants has never been explored. OBJECTIVES: To identify isolated CDH genetic causes, to fine map the mutational burden, and to search for a correlation between the genotype and the disease severity and outcome. METHODS: Targeted massively parallel sequencing of 143 human and mouse CDH causative and candidate genes in a cohort of 120 fetuses with isolated CDH and detailed outcome measures. RESULTS: Pathogenic and likely pathogenic variants were identified in 10% of the cohort. These variants affect both known CDH causative genes, namely, ZFPM2, GATA4, and NR2F2, and new genes, namely, TBX1, TBX5, GATA5, and PBX1. In addition, mutation burden analysis identified LBR, CTBP2, NSD1, MMP14, MYOD1, and EYA1 as candidate genes with enrichment in rare but predicted deleterious variants. No obvious correlation between the genotype and the phenotype or short-term outcome has been found. CONCLUSION: Targeted resequencing identifies a genetic cause in 10% of isolated CDH and identifies new candidate genes.

OBJECTIVE: New tools are required to improve the identification of women who are at increased risk for spontaneous preterm birth (sPTB). Quantitative analysis of tissue texture on ultrasound has been used to extract robust features from the ultrasound image to detect subtle changes in its microstructure. This may be applied to the cervix. The aim of this study was to determine if there is an association between quantitative analysis of cervical texture (CTx) on mid-trimester ultrasound and sPTB < 37 + 0 weeks' gestation. METHODS: This was a single-center nested case-control study of a prospective cohort of 677 consecutive women with singleton pregnancy assessed between 19 + 0 and 24 + 6 weeks' gestation. Women at increased risk for sPTB were included unless they received treatment to prevent sPTB. Women who delivered < 37 + 0 weeks (sPTB) were considered as cases and were matched in a 1: 10 ratio with randomly selected contemporary controls who delivered at term. For each woman, one ultrasound image of the cervix was obtained for which quality was assessed, cervical length (CL) measured offline and a region of interest in the midportion of the anterior cervical lip delineated for use in local binary patterns analysis of CTx. A learning algorithm was developed to obtain the combination of CTx features best associated with sPTB based on feature transformation and discriminant analysis regression. The ability of the learning algorithm to predict sPTB was evaluated using a leave-one-out cross-validation technique, which produced a CTx-based score for each participant. Receiver-operating characteristics (ROC) curves were produced and sensitivity, specificity, and positive and negative likelihood ratios were calculated for the optimal cut-off based on the ROC curve. The results were compared with those obtained for CL. Investigators studying the images were blinded to pregnancy outcome at all times. RESULTS: Images from 310 women (27 cases and 283 controls) were of sufficient quality and included in the study. Median CTx-based score was significantly lower in cases compared with controls (-1.01 vs -0.07, P = 0.0001). CTx-based score maintained its significant association with sPTB after adjusting for possible confounders (history of sPTB, conization or Müllerian malformation, and CL < 25 mm). CTx-based score was a better predictor of sPTB (AUC, 0.77; 95% CI, 0.66-0.87) than was CL (AUC, 0.60; 95% CI, 0.47-0.72) (P = 0.03). Median CL was similar for cases and controls (37.7 vs 38.6 mm, P = 0.26), although cases were more likely to have CL < 25 mm (18.5% vs 0.4%, P < 0.001). CONCLUSION: Quantitative analysis of CTx enables the extraction of information relevant to sPTB from ultrasound images to generate a CTx-based score that is associated independently with sPTB. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

We reviewed data from a cohort of fetuses with ureterocele diagnosed and operated prenatally in four fetal therapy centers. Inclusion criteria were (1) ureterocele confirmed on detailed fetal ultrasound examination, (2) absence of additional fetal malformations, and (3) fetal intervention to decompress the ureterocele with local institutional review boards' approval. Data on sonographic follow-up, obstetrical, neonatal outcome, and postnatal evaluation were collected. Ten cases of prenatally treated ureterocele are described. Six cases benefited from a fetoscopy for laser incision and decompression, two cases had an ultrasound guided puncture before resorting to a fetoscopy with laser incision, one case had a balloon catheterization under ultrasound guidance, and one case had an ultrasound-guided opening of the ureterocele with a laser fiber passed through a 20-gauge needle. Mean gestational age at diagnosis was 21.6 GW. Two cases underwent termination of pregnancy. The remaining eight cases recovered normal amniotic fluid volume and delivered a liveborn child at a mean gestational age of 38.6 GW with normal creatinine levels during the first week of life. Prenatal incision provided complete treatment of severely obstructive ureteroceles in 80% of the cases and allowed improvement of urinary electrolytes, renal size and echogenicity, bladder filling in all survivors, and recollection of normal amniotic fluid volume, in case of oligoanhydramnios. © 2017 John Wiley Sons, Ltd.

BACKGROUND: Isolated congenital diaphragmatic hernia defect allows viscera to herniate into the chest, competing for space with the developing lungs. At birth, pulmonary hypoplasia leads to respiratory insufficiency and persistent pulmonary hypertension that is lethal in up to 30% of patients. Antenatal measurement of lung size and liver herniation can predict survival after birth. Prenatal intervention aims at stimulating lung development, clinically achieved by percutaneous fetal endoscopic tracheal occlusion under local anesthesia. This in utero treatment requires a second intervention to reestablish the airway, either before birth or at delivery. OBJECTIVE: To describe our experience with in utero endotracheal balloon removal. MATERIALS AND METHODS: This is a retrospective analysis of prospectively collected data on consecutive patients with congenital diaphragmatic hernia treated in utero by fetal endoscopic tracheal occlusion from 3 centers. Maternal and pregnancy-associated variables were retrieved. Balloon removal attempts were categorized as elective or emergency and by technique (in utero: ultrasound-guided puncture; fetoscopy; ex utero: on placental circulation or postnatal tracheoscopy). RESULTS: We performed 351 balloon insertions during a 144-month period. In 9 cases removal was attempted outside fetal endoscopic tracheal occlusion centers, 3 of which were deemed impossible and led to neonatal death. We attempted 302 in-house balloon removals in 292 fetuses (217 elective [71.8%], 85 emergency [28.2%]) at 33.4 ± 0.1 weeks (range: 28.9-37.1), with a mean interval to delivery of 16.6 ± 0.8 days (0-85). Primary attempt was by fetoscopy in 196 (67.1%), by ultrasound-guided puncture in 62 (21.2%), by tracheoscopy on placental circulation in 30 (10.3%), and postnatal tracheoscopy in 4 cases (1.4%); a second attempt was required in 10 (3.4%) cases. Each center had different preferences for primary technique selection. In elective removals, we found no differences in the interval to delivery between fetoscopic and ultrasound-guided puncture removals. Difficulties during fetoscopic removal led to the development of a stylet to puncture the balloon, leading to shorter operating time and easier reestablishment of airways. CONCLUSION: In these fetal treatment centers, the balloon could always be removed successfully. In 90% this was in utero, with the use of fetoscopy preferred over ultrasound-guided puncture. Ex utero removal was a fall-back procedure. In utero removal does not seem to precipitate immediate membrane rupture, labor, or delivery, although the design of the study did not allow for a formal conclusion. For fetoscopic removals, the introduction of a stylet facilitated retrieval. Successful removal may rely on a permanently prepared team with expertise in all possible techniques.

Context: Surgical nonautologous meshes have been used for several decades to repair abdominal wall herniae. Implantable materials have been adopted for the treatment of female and male stress urinary incontinence (SUI) and female pelvic organ prolapse (POP). Objective: A consensus review of existing data based on published meta-analyses and reviews. Evidence acquisition: This document summarises the deliberations of a consensus group meeting convened by the European Association of Urology (EAU) and the European Urogynecological Association, to explore the current evidence relating to the use of polypropylene (PP) materials used for the treatment of SUI and POP, with reference to the 2016 EAU guidelines (European Association of Urology 2016), the European Commission's SCENIHR report on the use of surgical meshes (SCENIHR 2015), other available high-quality evidence, guidelines, and national recommendations. Evidence synthesis: Current data suggest that the use of nonautologous durable materials in surgery has well-established benefits but significant risks, which are specific to the condition and location they are used for. Various graft-related complications have been described-such as infection, chronic pain including dyspareunia, exposure in the vagina, shrinkage, erosion into other organs of xenografts, synthetic PP tapes (used in SUI), and meshes (used in POP)-which differ from the complications seen with abdominal herniae. Conclusions: When considering surgery for SUI, it is essential to evaluate the available options, which may include synthetic midurethral slings (MUSs) using PP tapes, bulking agents, colposuspension, and autologous sling surgery. The use of synthetic MUSs for surgical treatment of SUI in both male and female patients has good efficacy and acceptable morbidity. Synthetic mesh for POP should be used only in complex cases with recurrent prolapse in the same compartment and restricted to those surgeons with appropriate training who are working in multidisciplinary referral centres. Patient summary: Synthetic slings can be safely used in the surgical treatment of stress incontinence in both male and female patients. Patients need to be aware of the alternative therapy and potential risks and complications of this therapy. Synthetic mesh for treating prolapse should be used only in complex cases with recurrent prolapse in specialist referral centres. (C) 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Contains fulltext : 168576.pdf (Publisher’s version ) (Open Access) In 2010, the congenital diaphragmatic hernia (CDH) EURO Consortium published a standardized neonatal treatment protocol. Five years later, the number of participating centers has been raised from 13 to 22. In this article the relevant literature is updated, and consensus has been reached between the members of the CDH EURO Consortium. Key updated recommendations are: (1) planned delivery after a gestational age of 39 weeks in a high-volume tertiary center; (2) neuromuscular blocking agents to be avoided during initial treatment in the delivery room; (3) adapt treatment to reach a preductal saturation of between 80 and 95% and postductal saturation >70%; (4) target PaCO2 to be between 50 and 70 mm Hg; (5) conventional mechanical ventilation to be the optimal initial ventilation strategy, and (6) intravenous sildenafil to be considered in CDH patients with severe pulmonary hypertension. This article represents the current opinion of all consortium members in Europe for the optimal neonatal treatment of CDH.

To create a semi-automated outlining tool for the levator hiatus, to reduce interobserver variability and and speed up analysis.The proposed automated hiatus segmentation (AHS) algorithm takes a C-plane image, in the plane of minimal hiatal dimensions, and manually defined vertical hiatal limits as input. The AHS then creates an initial outline by fitting predefined templates on an intensity-invariant edge map, which is further refined using the B-spline explicit active surfaces framework. The AHS was tested using 91 representative C-plane images. Reference hiatal outlines were obtained manually and compared with the AHS outlines by three independent observers. The mean absolute distance (MAD), Hausdorff distance and Dice and Jaccard coefficients were used to quantify segmentation accuracy. Each of these metrics was calculated both for computer-observer differences (COD) and for interobserver differences. The Williams index was used to test the null hypothesis that the automated method would agree with the operators at least as well as the operators agreed with each other. Agreement between the two methods was assessed using the intraclass correlation coefficient (ICC) and Bland-Altman plots.The AHS contours matched well with the manual ones (median COD, 2.10 (interquartile range (IQR), 1.54) mm for MAD). The Williams index was greater than or close to 1 for all quality metrics, indicating that the algorithm performed at least as well as did the manual references in terms of interrater variability. The interobserver differences using each of the metrics were significantly lower, and a higher ICC was achieved (0.93), when obtaining outlines using the AHS compared with manually. The Bland-Altman plots showed negligible bias between the two methods. Using the AHS took a median time of 7.07 (IQR, 3.49) s, while manual outlining took 21.31 (IQR, 5.43) s, thus being almost three-fold faster. Using the AHS, in general, the hiatus could be outlined completely using only three points, two for initialization and one for manual adjustment.We present a method for tracing the levator hiatal outline with minimal user input. The AHS is fast, robust and reliable and improves interrater agreement. Copyright © 2015 ISUOG. Published by John WileySons Ltd.

We aimed to assess in vivo changes in lung and liver volumes in fetuses with isolated congenital diaphragmatic hernia, either expectantly managed or treated in utero.

Congenital diaphragmatic hernia (CDH) may be isolated or associated with other structural anomalies, the latter with poor prognosis. The defect allows viscera to herniate through the defect into the chest, competing for space with the developing lungs. At birth, pulmonary hypoplasia leads to respiratory insufficiency and persistent pulmonary hypertension that is lethal in up to 30% of patients. When isolated, survival chances can be predicted by antenatal measurement of lung size and liver herniation. Chromosomal microarrays and exome sequencing contribute to understanding genetic factors underlying isolated CDH. Prenatal intervention aims at stimulating lung development, clinically achieved by percutaneous fetal endoscopic tracheal occlusion (FETO) under local anesthesia. The Tracheal Occlusion To Accelerate Lung growth trial (www.totaltrial.eu) is an international randomized trial investigating the role of fetal therapy for severe and moderate pulmonary hypoplasia. Despite an apparent increase in survival following FETO, the search for lesser invasive and more potent prenatal interventions must continue.

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Objectives To describe the true incidence, prenatal detection rate and fetal outcome of congenital diaphragmatic hernia (CDH) in a systematically registered population over an 18-year period and to determine any change in trends over time. Methods This was a retrospective study of all cases of CDH registered in the Central-Eastern France Birth Defects Registry from 1986 to 2003. All fetuses and infants up to 1 year of age diagnosed with CDH were registered, including miscarriages later than 22 weeks of gestation, stillbirths and terminations of pregnancy (TOP). Routine prenatal screening consisted of three ultrasound examinations and there was no upper limit of gestational age for TOP. Results Five hundred and one cases of CDH were identified from a total of 1 835 022 live births (2.7 cases per 10 000 live births). The overall prenatal detection rate was 54%. There was a significant increase over time in the detection rate mainly for associated CDH and left-sided CDH (P < 0.0001), and in the proportion of neonates delivered in tertiary centers (P < 0.0001). The overall survival rate at discharge was 47% and this increased significantly over time for isolated CDH (P = 0.04), whereas it was lower and remained stable for associated CDH (P = 0.64). The TOP rate for isolated CDH did not vary significantly in contrast to that for associated CDH cases in which the TOP rate increased over time, progressively replacing the neonatal death rate (P = 0.01). Conclusions Over an 18-year period, this large population-based study demonstrated increasing prenatal detection rates for associated CDH and left-sided CDH and confirmed an increasing survival rate mainly for isolated CDH. Copyright  2006 ISUOG. Published by John Wiley & Sons, Ltd.

Eighty-eight endometrial specimens from 36 postmenopausal breast cancer patients treated with tamoxifen were investigated cytogenetically and molecularly using fluorescence in situ hybridization with appropriate probes for the HMGIC and HMGIY genes. Twenty control specimens, 10 endometrial polyps, and 10 endometrial biopsy specimens were investigated in the same way. Of the 88 specimens, 44 were from endometrial polyps; 3 were from endocervical polyps; 7 were from cystic endometrium; 30 were from normal or atrophic endometrium, normal endocervix, or myometrium; and 4 were from endometrial carcinomas. Chromosome investigation of the endometrial polyps showed the nature of the chromosome changes in tamoxifen-induced polyps to be the same as that in the controls and in sporadic endometrial polyps described in the literature. HMGIC and HMGIY gene rearrangements in both groups were identical as shown by fluorescence in situ hybridization, which also allowed for the detection of seven hidden paracentric inversions involving 12q15, one of which occurred in a cystic endometrium. The carcinomas did not exhibit any of these changes. Because abnormal expression of HMGIC or HMGIY as a consequence of structural chromosome changes in 12q15 or 6p21, respectively, is invariably associated with benign neoplasia, tamoxifen-associated endometrial polyps are unlikely to undergo further malignant transformation, and a mode of action of tamoxifen as an external carcinogen is unlikely.

Background: Amniotic fluid (AF) cell populations will be applied in perinatology. We aimed to test the feasibility of large-scale cell expansion. Study Methods: We determined the best out of three published expansion protocols for mesenchymal progenitors (AF samples, n = 4) in terms of self-renewal ability. Characterization was performed based on morphology, surface marker analysis, cytogenetic stability, and differentiation potential. The conditions for the best self-renewal ability were further determined in a consecutive series (n = 159). Results: The medium containing fetal bovine serum (FBS), epidermal growth factor, insulin, transferrin, and tri-iodothyronine, combined with seeding on gelatin-coated wells, best stimulated the growth of cells with mesenchymal features, as demonstrated by flow cytometry; however, only osteogenic differentiation was possible. Large-scale testing (n = 44) failed to confirm a robust self-renewal ability. Better results were obtained (n = 88) using optimized FBS or an increased initial cell density. Eventually over 81% of cultures continued growing after the initial medium change and had mesenchymal features but failed differentiation assays. Discussion: Routine in vitro expansion of AF-derived mesenchymal cells remains problematic. Despite an increase in successful cell cultures from 40 up to 80% using optimized serum and an increased cell density, eventually cells failed to demonstrate differentiation abilities. Routine isolation and expansion from unselected AF samples remains a challenge.