Julio Jimenez

Fetoscopic versus Open Repair for Spina Bifida Aperta: A Systematic Review of Outcomes.

Objective: To compare outcomes of fetoscopic spina bifida aperta repair (FSBAR) with the results of the open approach (OSBAR) as in the Management Of Myelomeningocele Study (MOMS). Methods: This was a systematic comparison of reports on FSBAR with data from the MOMS (n = 78). Inclusion criteria were studies of spina bifida aperta patients who underwent FSBAR and were followed for ≥12 months. Primary outcome was perinatal mortality. Secondary outcomes included operative, maternal, fetal, neonatal and infant outcomes. Results: Out of 16 reports, we included 5 from 2 centers. Due to bias and heterogeneity, analysis was restricted to two overlapping case series (n = 51 and 71). In those, FSBAR was technically different from OSBAR, had comparable perinatal mortality (7.8 vs. 2.6%, p = 0.212) and shunt rate at 12 months (45 vs. 40%, p = 0.619), longer operation time (223 vs. 105 min, p < 0.001), higher preterm prelabor membrane rupture rate (84 vs. 46%, p < 0.001), earlier gestational age at birth (32.9 vs. 34.1 weeks, p = 0.03), higher postnatal reoperation rate (28 vs. 2.56%, p < 0.001) and absence of uterine thinning or dehiscence (0 vs. 36%, p < 0.001). Functional outcomes were not available. Conclusion: FSBAR utilizes a different neurosurgical technique, takes longer to complete, induces more prematurity, requires additional postnatal procedures, yet has a comparable shunt rate and is not associated with uterine thinning or dehiscence. Long-term functional data are awaited.

Transplacental sildenafil rescues lung abnormalities in the rabbit model of diaphragmatic hernia

Introduction The management of congenital diaphragmatic hernia (DH) would benefit from an antenatal medical therapy, which addresses both lung hypoplasia and persistent pulmonary hypertension. We aimed at evaluating the pulmonary effects of sildenafil in the fetal rabbit model for DH. Methods We performed a dose-finding study to achieve therapeutic fetal plasmatic concentrations without toxicity following maternal sildenafil administration. Subsequently, DH fetuses were randomly exposed to transplacental placebo or sildenafil 10 mg/kg/day from gestational day 24 until examination at term (day 30). Efficacy measures were ipsilateral pulmonary vascular and airway morphometry, micro-CT-based branching analysis, Doppler flow in the main pulmonary artery and postnatal lung mechanics. Results Fetal sildenafil plasmatic concentration was above the minimal therapeutic level for at least 22 h/day without maternal and fetal side effects. The placebo-exposed DH fetuses had increased wall thickness in peripheral pulmonary vessels and significantly less fifth-order vessels compared with controls (CTR). Sildenafil-exposed DH fetuses, instead, had a medial and adventitial thickness in peripheral pulmonary vessels in the normal range and normal vascular branching. Fetal pulmonary artery Doppler showed a reduction of pulmonary vascular resistances both in DH and in CTR fetuses treated by sildenafil compared with the placebo-treated ones. Sildenafil also reversed the mean terminal bronchiolar density to normal and improved lung mechanics, yet without measurable impact on lung-to-bodyweight ratio. Conclusions In the rabbit model for DH, antenatal sildenafil rescues vascular branching and architecture, reduces pulmonary vascular resistances and also improves airway morphometry and respiratory mechanics.

Transcriptome Analysis of the Preterm Rabbit Lung after Seven Days of Hyperoxic Exposure

The neonatal management of preterm born infants often results in damage to the developing lung and subsequent morbidity, referred to as bronchopulmonary dysplasia (BPD). Animal models may help in understanding the molecular processes involved in this condition and define therapeutic targets. Our goal was to identify molecular pathways using the earlier described preterm rabbit model of hyperoxia induced lung-injury. Transcriptome analysis by mRNA-sequencing was performed on lungs from preterm rabbit pups born at day 28 of gestation (term: 31 days) and kept in hyperoxia (95% O2) for 7 days. Controls were preterm pups kept in normoxia. Transcriptomic data were analyzed using Array Studio and Ingenuity Pathway Analysis (IPA), in order to identify the central molecules responsible for the observed transcriptional changes. We detected 2217 significantly dysregulated transcripts following hyperoxia, of which 90% could be identified. Major pathophysiological dysregulations were found in inflammation, lung development, vascular development and reactive oxygen species (ROS) metabolism. To conclude, amongst the many dysregulated transcripts, major changes were found in the inflammatory, oxidative stress and lung developmental pathways. This information may be used for the generation of new treatment hypotheses for hyperoxia-induced lung injury and BPD.

Caffeine Prevents Hyperoxia-Induced Functional and Structural Lung Damage in Preterm Rabbits.

Background: Caffeine is a commonly used drug for apnea of prematurity. It may, however, also have a beneficial effect on bronchopulmonary dysplasia (BPD), which is the most common complication of extreme preterm birth. Objectives: To study the inflammatory, structural and functional effects of caffeine in an animal model of BPD. Methods: Preterm New Zealand-Dendermonde rabbits (gestational day 28; term 31) were randomized to three groups: normoxia-placebo (N-P), hyperoxia-placebo (H-P) and hyperoxia-caffeine (H-C). Lung function was assessed on postnatal day 5, along with airway morphometry, vascular morphometry and a score observing airway inflammation. Results: Caffeine improved lung function by increasing lung volume [mean displaced volume N-P: 40.1 ± 6 ml/kg, H-P: 27.8 ± 8 ml/kg and H-C: 34.4 ± 7 ml/kg (p < 0.05); total lung capacity: N-P: 1.17 ± 0.1 ml, H-P: 0.67 ± 0.1 ml and H-C: 1.1 ± 0.1 ml (p < 0.05)], decreasing tissue damping [N-P: 2.7 ± 0.3 cm H2O/ml, H-P: 4.6 ± 0.6 cm H2O/ml and H-C: 3.2 ± 0.4 cm H2O/ml (p < 0.05)], elastance [N-P: 9.3 ± 2.4 cm H2O/ml, H-P: 19.2 ± 7.4 cm H2O/ml and H-C: 10.7 ± 2 cm H2O/ml (p < 0.05)] and compliance [N-P: 0.06 ± 0.01 cm H2O/ml, H-P: 0.054 ± 0.01 cm H2O/ml and H-C: 0.07 ± 0.013 cm H2O/ml (p < 0.05)]. Caffeine also improved histology by decreasing alveolar size [linear intercepts; N-P: 83.6 ± 1.7, H-P: 82.9 ± 1.6 and H-C: 67.3 ± 1.4 (p < 0.05)], increasing radial alveolar count (N-P: 6.6 ± 0.5, H-P: 5.7 ± 0.6 and H-C: 7.05 ± 0.5) and decreasing the acute inflammation score [N-P: 0.3 ± 0.1, H-P: 0.5 ± 0.1 and H-C: 0.4 ± 0.1 (p < 0.05)]. Conclusion: In preterm rabbits, caffeine reduces the functional, architectural and inflammatory pulmonary changes induced by hyperoxia in the lung.

Balloon removal after fetoscopic endoluminal tracheal occlusion for congenital diaphragmatic hernia

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.

Presence of an Immune System Increases Anti‐Tumor Effect of Ag Nanoparticle Treated Mice

To date, most nanomedical studies rely on the use of immune-deficient mice in which the contribution of the immune system on the applied therapy is ignored. Here, the degradation of silver nanoparticles (Ag NPs) is exploited as a means to treat subcutaneous tumor models in mice. To investigate the impact of the immune system, the same tumor cell type (KLN 205 murine squamous cell carcinoma) is used in a xenograft model in NOD SCIDγ immune-deficient mice and as a syngeneic model in immune-competent DBA/2 mice. The Ag NPs are screened for their cytotoxicity on various cancer cell lines, indicating a concentration-dependent induction of oxidative stress, mitochondrial damage, and autophagy on all cell types tested. At subcytotoxic concentrations, prolonged cellular exposure to the Ag NPs results in toxicity due to NP degradation and the generation of toxic Ag+ ions. At subcytotoxic conditions, the NPs are found to cause inflammation in vitro. Similar results are obtained in the immune-competent mouse model, where clear inflammation is observed after treatment of the implanted tumors with Ag NPs. This inflammation leads to an ongoing antitumoral effect, which results in a significantly reduced tumor growth compared to Ag NP-treated tumors in an immune-deficient model.

Medical and Regenerative Solutions for Congenital Diaphragmatic Hernia: A Perinatal Perspective

In the EU-27, 2,100 babies with congenital diaphragmatic hernia (CDH) are born annually. CDH is fatal in 30% of them. Experimental fetal surgery in severe cases results in a survival rate of 50 to 60% at its best. Failure is due to insufficient lung growth, persistent pulmonary hypertension or prematurity induced by the procedure. For nonsurvivors alternative strategies are required. Survivors undergo anatomical repair, but large diaphragmatic defects are closed using a patch. At present the used materials are less than ideal, mainly because of recurrence and chest deformation. To overcome the above limitations, alternative medical therapies (pharmacologic or cell therapy) that are more potent and less invasive are needed. Also a more functional postnatal repair may be possible when using novel scaffolds or engineered constructs. We see a prominent place for autologous amniotic fluid-derived stem cells for these novel strategies, which could be prenatally harvested following appropriate patient selection by noninvasive imaging.

Preclinical evaluation of cell-based strategies to prevent or treat bronchopulmonary dysplasia in animal models: a systematic review

Abstract Bronchopulmonary dysplasia (BPD) remains the most common complication of extreme prematurity as no effective treatment is available to date. This calls for the exploration of new therapeutic options like cell therapy, which is already effective for various human (lung) disorders. We systematically searched the MEDLINE, Embase, and Web of Science databases from the earliest date till January 2017 and included original studies on the perinatal use of cell-based therapies (i.e. cells and/or cell-derivatives) to treat BDP in animal models. Fourth publications describing 47 interventions were retrieved. Newborn mice/rats raised in a hyperoxic environment were studied in most interventions. Different cell types – either intact cells or their conditioned medium – were administered, but bone marrow and umbilical cord blood derived mesenchymal stem cells were most prevalent. All studies reported positive effects on outcome parameters including alveolar and vascular morphometry, lung function, and inflammation. Cell homing to the lungs was demonstrated in some studies, but the therapeutic effects seemed to be mostly mediated via paracrine modulation of inflammation, fibrosis and angiogenesis. Conclusion: Multiple rat/mouse studies show promise for cell therapy for BPD. Yet careful study of action mechanisms and side effects in large animal models is imperative before clinical translation can be achieved.

In vivo evidence by magnetic resonance volumetry of a gestational age dependent response to tracheal occlusion for congenital diaphragmatic hernia

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.

The Effect of Transplacental Administration of Glucagon-Like Peptide-1 on Fetal Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia

Objective: Glucagon-like peptide-1 (GLP-1) increases surfactant protein expression in type 2 pneumocytes. Herein, we determine if transplacental GLP-1 treatment accelerates lung growth in the fetal rabbit model of congenital diaphragmatic hernia (DH). Methods: Time-mated does had an induction of DH on day 23 followed by daily GLP-1 or placebo injection until term. At that time, the does were weighed, fetal blood was obtained for GLP-1 assay, and the lungs were dissected. Fetal outcome measures were lung-to-body-weight ratio (LBWR), morphometry, and Ki67 and surfactant protein B (SPB) expression. Results: Maternal weight loss in the GLP-1 group was 7.1%. Fetal survival was lower in GLP-1 fetuses compared to placebo controls (27/85, 32% vs. 35/57, 61%; p < 0.05). Fetal GLP-1 levels were increased 3.6-fold. The LBWR of GLP-1 DH fetuses fell within the range of DH placebo fetuses (1.166 ± 0.207% vs. 1.312 ± 0.418%), being significantly lower than that of placebo-exposed unoperated fetuses (2.280 ± 0.522%; p < 0.001). GLP-1 did not improve airway morphometry. GLP-1 DH lungs had a reduced adventitial and medial thickness within the range of controls, and lesser muscularization of vessels measuring 30-60 µm. There were no differences in Ki67 and SPB expression. Conclusion: GLP-1 at this dosage improves peripheric pulmonary vessel morphology in intra-acinar vessels with no effect on airway morphometry but with significant maternal and fetal side effects. Thus, it is an unlikely medical strategy.