PAK3 activation promotes the tangential to radial migration switch of cortical interneurons by increasing leading process dynamics and disrupting cell polarity.

Mutations of PAK3, a p21-activated kinase, are associated in humans with cognitive deficits suggestive of defective cortical circuits and with frequent brain structural abnormalities. Most human variants no longer exhibit kinase activity. Since GABAergic interneurons express PAK3 as they migrate within the cortex, we here examined the role of PAK3 kinase activity in the regulation of cortical interneuron migration. During the embryonic development, cortical interneurons migrate a long distance tangentially and then re-orient radially to settle in the cortical plate, where they contribute to cortical circuits. We showed that interneurons expressing a constitutively kinase active PAK3 variant (PAK3-ca) extended shorter leading processes and exhibited unstable polarity. In the upper cortical layers, they entered the cortical plate and extended radially oriented processes. In the deep cortical layers, they exhibited erratic non-processive migration movements and accumulated in the deep pathway. Pharmacological inhibition of PAK3 kinase inhibited the radial migration switch of interneurons to the cortical plate and reduced their accumulation in the deep cortical layers. Interneurons expressing a kinase dead PAK3 variant (PAK3-kd) developed branched leading processes, maintained the same polarity during migration and exhibited processive and tangentially oriented movements in the cortex. These results reveal that PAK3 kinase activity, by promoting leading process shortening and cell polarity changes, inhibits the tangential processive migration of interneurons and favors their radial re- orientation and targeting to the cortical plate. They suggest that patients expressing PAK3 variants with impaired kinase activity likely present alterations in the cortical targeting of their GABAergic interneurons.

Quantitative live imaging reveals a direct interaction between CD44v6 and MET in membrane domains upon activation with both MET ligands, HGF and internalin B.

Deregulation of the receptor tyrosine kinase MET/hepatocyte growth factor (HGF) pathway results in several pathological processes involved in tumor progression and metastasis. In a different context, MET can serve as an entry point for the bacterium Listeria monocytogenes, when activated by the internalin B (InlB) protein during infection of non-phagocytic cells. We have previously demonstrated that MET requires CD44v6 for its ligand-induced activation. However, the stoichiometry and the steps required for the formation of this complex, are still unknown. In this work, we studied the dynamics of the ligand-induced interaction of CD44v6 with MET at the plasma membrane. Using Förster resonance energy transfer-based fluorescence lifetime imaging microscopy in T-47D cells, we evidenced a direct interaction between MET and CD44v6 promoted by HGF and InlB in live cells. In the absence of MET, fluorescence correlation spectroscopy experiments further showed the dimerization of CD44v6 and the increase of its diffusion induced by HGF and InlB. In the presence of MET, stimulation of the cells by HGF or InlB significantly decreased the diffusion of CD44v6, in line with the formation of a ternary complex of MET with CD44v6 and HGF/InlB. Finally, similarly to HGF/InlB, disruption of liquid-ordered domains (Lo) by methyl-ß-cyclodextrin increased CD44v6 mobility suggesting that these factors induce the exit of CD44v6 from the Lo domains. Our data led us to propose a model for MET activation, where CD44v6 dimerizes and diffuses rapidly out of Lo domains to form an oligomeric MET/ligand/CD44v6 complex that is instrumental for MET activation.

Identification of an Imidazopyridine-based Compound as an Oral Selective Estrogen Receptor Degrader for Breast Cancer Therapy.

The pro-oncogenic activities of estrogen receptor alpha (ERα) drive breast cancer pathogenesis. Endocrine therapies that impair the production of estrogen or the action of the ERα are therefore used to prevent primary disease metastasis. Although recent successes with ERα degraders have been reported, there is still the need to develop further ERα antagonists with additional properties for breast cancer therapy. We have previously described a benzothiazole compound A4B17 that inhibits the proliferation of androgen receptor-positive prostate cancer cells by disrupting the interaction of the cochaperone BAG1 with the AR. A4B17 was also found to inhibit the proliferation of estrogen receptor-positive (ER+) breast cancer cells. Using a scaffold hopping approach, we report here a group of small molecules with imidazopyridine scaffolds that are more potent and efficacious than A4B17. The prototype molecule X15695 efficiently degraded ERα and attenuated estrogen-mediated target gene expression as well as transactivation by the AR. X15695 also disrupted key cellular protein-protein interactions such as BAG1-mortalin (GRP75) interaction as well as wild-type p53-mortalin or mutant p53-BAG2 interactions. These activities together reactivated p53 and resulted in cell-cycle block and the induction of apoptosis. When administered orally to in vivo tumor xenograft models, X15695 potently inhibited the growth of breast tumor cells but less efficiently the growth of prostate tumor cells. We therefore identify X15695 as an oral selective ER degrader and propose further development of this compound for therapy of ER+ breast cancers. Significance: An imidazopyridine that selectively degrades ERα and is orally bioavailable has been identified for the development of ER+ breast cancer therapeutics. This compound also activates wild-type p53 and disrupts the gain-of-function tumorigenic activity of mutant p53, resulting in cell-cycle arrest and the induction of apoptosis.

Combined esophageal and duodenal atresia: A review of the literature from 1950 to 2020.

The combination of duodenal atresia (DA) and esophageal atresia (EA) is very rare. With improvements in prenatal sonography and the use of fetal magnetic resonance imaging (MRI), these malformations can be diagnosed in a more accurate and timely manner; polyhydramnios remains the most common sign despite having a low specificity. The high rate of associated anomalies (in 85% of cases) can also impact neonatal management and increase the morbidity rate; thus, it is of paramount importance to look for every possible associated malformation, such as VACTERL and chromosomic anomalies. The surgical management of this combination of atresias is not well defined and changes according to the patient's clinical status, the type of EA, and the other associated malformations. Management ranges from a primary approach for one of the atresias with delayed correction of the other (56.8%) to a simultaneous repair of both atresias (33.8%) with or without gastrostomy, or total abstention (9.4%). We suggest that a simultaneous approach can be safely performed on patients in good physical condition, with a birth weight over 1500 g, and with no major respiratory distress; this method begins by closing the tracheoesophageal fistula to protect the lung and then repairing the DA. The mortality rate has decreased over the years, dropping from 71% before 1980 to 24% after 2001. In this review, we present the available evidence on these conditions, focusing mostly on the epidemiology, prenatal diagnosis, neonatal management strategies, and outcome, with the aim of determining how the different clinical features and surgical approaches may impact on morbidity and mortality.

Usefulness of routine early œsophagogram after primary repair of œsophageal atresia: a multicenter study.

BACKGROUND: Advances in surgical and neonatal care have led to improved survival of patients with œsophageal atresia (OA) over time. Morbidity remains significant, with one-third of patients being affected by a postoperative complication. Several aspects of management are not consensual, such as the use of œsophagogram before starting oral feeding. METHODS: We conducted a multicenter retrospective study, including all children with OA that underwent a primary anastomosis in the first days of life, between 2012 and 2018 in five French centers, to determine the usefulness of postoperative œsophagogram during the 10 days after early primary repair of OA to diagnose the anastomotic leak and congenital œsophageal stenosis. RESULTS: Among 225 included children, 90 (40%) had a routine œsophagogram and 25 (11%) had an anastomotic leak, clinically diagnosed before the scheduled œsophagogram in 24/25 (96%) children at median postoperative day 4. Ten patients had associated congenital œsophageal stenosis diagnosed on the œsophagogram in only 30% of cases. CONCLUSION: Early œsophagogram is rarely useful in the diagnosis of an anastomotic leak, which is clinically diagnosed before performing an œsophagogram in the majority of cases. The need for a postoperative œsophagogram should be evaluated on a case-by-case basis. IMPACT: Early œsophagogram is not helpful in the diagnosis of an anastomotic leak in the majority of cases. An anastomotic leak is most often diagnosed clinically before performing an œsophagogram. Early postoperative œsophagogram could be helpful for the diagnosis of congenital œsophageal stenosis. However, dysphagia occurs later and early diagnosis of congenital œsophageal stenosis has no impact on the management and outcome of asymptomatic children. Indication of postoperative œsophagogram has to be evaluated on a case-by-case basis.

The molecular basis of p21-activated kinase-associated neurodevelopmental disorders: From genotype to phenotype.

Although the identification of numerous genes involved in neurodevelopmental disorders (NDDs) has reshaped our understanding of their etiology, there are still major obstacles in the way of developing therapeutic solutions for intellectual disability (ID) and other NDDs. These include extensive clinical and genetic heterogeneity, rarity of recurrent pathogenic variants, and comorbidity with other psychiatric traits. Moreover, a large intragenic mutational landscape is at play in some NDDs, leading to a broad range of clinical symptoms. Such diversity of symptoms is due to the different effects DNA variations have on protein functions and their impacts on downstream biological processes. The type of functional alterations, such as loss or gain of function, and interference with signaling pathways, has yet to be correlated with clinical symptoms for most genes. This review aims at discussing our current understanding of how the molecular changes of group I p21-activated kinases (PAK1, 2 and 3), which are essential actors of brain development and function; contribute to a broad clinical spectrum of NDDs. Identifying differences in PAK structure, regulation and spatio-temporal expression may help understanding the specific functions of each group I PAK. Deciphering how each variation type affects these parameters will help uncover the mechanisms underlying mutation pathogenicity. This is a prerequisite for the development of personalized therapeutic approaches.

Automated high-throughput image processing as part of the screening platform for personalized oncology.

Cancer is a devastating disease and the second leading cause of death worldwide. However, the development of resistance to current therapies is making cancer treatment more difficult. Combining the multi-omics data of individual tumors with information on their in-vitro Drug Sensitivity and Resistance Test (DSRT) can help to determine the appropriate therapy for each patient. Miniaturized high-throughput technologies, such as the droplet microarray, enable personalized oncology. We are developing a platform that incorporates DSRT profiling workflows from minute amounts of cellular material and reagents. Experimental results often rely on image-based readout techniques, where images are often constructed in grid-like structures with heterogeneous image processing targets. However, manual image analysis is time-consuming, not reproducible, and impossible for high-throughput experiments due to the amount of data generated. Therefore, automated image processing solutions are an essential component of a screening platform for personalized oncology. We present our comprehensive concept that considers assisted image annotation, algorithms for image processing of grid-like high-throughput experiments, and enhanced learning processes. In addition, the concept includes the deployment of processing pipelines. Details of the computation and implementation are presented. In particular, we outline solutions for linking automated image processing for personalized oncology with high-performance computing. Finally, we demonstrate the advantages of our proposal, using image data from heterogeneous practical experiments and challenges.

Peri- and neonatal factors influencing mortality and morbidity 2 years after esophageal atresia primary repair: a single center retrospective study.

Long-term digestive, respiratory, and neurological morbidity is significant in children who have undergone surgery for esophageal atresia (EA), especially after staged repair for long-gap EA. Risk factors for morbidity after primary repair (non-long-gap populations) have been less documented. We investigated peri- and neonatal factors associated with unfavorable outcomes in children 2 years after primary esophageal anastomosis. This was a single-center retrospective study, based on neonatal, surgical, and pediatric records of children born between December 1, 2002, and December 31, 2018, and followed up to age 2 years. The primary endpoint was unfavorable outcome at 2 years of age, defined by death or survival with severe respiratory, digestive, or neurologic morbidity. Univariate analyses followed by logistic regression analyses were performed to identify the peri- and neonatal risk factors of unfavorable outcomes among survivors at discharge. A total of 150 neonates were included (mean birth weight 2520 ± 718 g, associated malformations 61%); at age 2, 45 (30%) had one or more severe morbidities and 11 had died during the neonatal stay and 2 after discharge (8.7% deaths). In multivariate analyses of the 139 survivors at discharge, duration of ventilatory support (invasive and non-invasive) for more than 8 days (OR 3.74; CI95% [1.68-8.60]; p = 0.001) and achievement of full oral feeding before hospital discharge (OR 0.20; CI95% [0.06-0.56]; p = 0.003) were independently associated with adverse outcome after adjustment for sex, preterm birth, associated heart defect, any surgical complication, and the occurrence of more than one nosocomial infections during the neonatal stay. CONCLUSIONS: Post-operative ventilation and feeding management strategies may represent an opportunity for quality-of-care improvement to positively impact long-term outcomes after primary esophageal atresia repair. WHAT IS KNOWN: • Children operated on for esophageal atresia experience long-term digestive, respiratory, and neurologic morbidity, especially after multiple-stage esophageal repair. • Exclusive oral feeding at discharge is associated with a decreased risk of medical complications in the first years of life, in studies including all types of esophageal atresia repair. Outcomes of children after primary repair (non-long gap populations) have been less documented. WHAT IS NEW: • In our retrospective cohort of children with one-stage esophageal atresia repair, ventilatory support for more than 8 days and inability to achieve full oral feeding before hospital discharge in the neonatal period were independently associated with adverse digestive, respiratory, and neurologic outcomes at 2 years in survivors. • Both these factors are potentially modifiable, representing an opportunity for quality-of-care improvement to positively impact long-term outcomes. These results might also help identify children at risk of unfavorable evolution, to customize a multi-disciplinary follow-up program.

Challenges in glioblastoma research: focus on the tumor microenvironment.

Glioblastoma (GBM) is the most deadly type of malignant brain tumor, despite extensive molecular analyses of GBM cells. In recent years, the tumor microenvironment (TME) has been recognized as an important player and therapeutic target in GBM. However, there is a need for a full and integrated understanding of the different cellular and molecular components involved in the GBM TME and their interactions for the development of more efficient therapies. In this review, we provide a comprehensive report of the GBM TME, which assembles the contributions of physicians and translational researchers working on brain tumor pathology and therapy in France. We propose a holistic view of the subject by delineating the specific features of the GBM TME at the cellular, molecular, and therapeutic levels.

Retrospective evaluation of clinical and molecular data of 148 cases of esophageal atresia.

Developmental abnormalities provide a unique opportunity to seek for the molecular mechanisms underlying human organogenesis. Esophageal development remains incompletely understood and elucidating causes for esophageal atresia (EA) in humans would contribute to achieve a better comprehension. Prenatal detection, syndromic classification, molecular diagnosis, and prognostic factors in EA are challenging. Some syndromes have been described to frequently include EA, such as CHARGE, EFTUD2-mandibulofacial dysostosis, Feingold syndrome, trisomy 18, and Fanconi anemia. However, no molecular diagnosis is made in most cases, including frequent associations, such as Vertebral-Anal-Cardiac-Tracheo-Esophageal-Renal-Limb defects (VACTERL). This study evaluates the clinical and genetic test results of 139 neonates and 9 fetuses followed-up at the Necker-Enfants Malades Hospital over a 10-years period. Overall, 52 cases were isolated EA (35%), and 96 were associated with other anomalies (65%). The latter group is divided into three subgroups: EA with a known genomic cause (9/148, 6%); EA with Vertebral-Anal-Cardiac-Tracheo-Esophageal-Renal-Limb defects (VACTERL) or VACTERL/Oculo-Auriculo-Vertebral Dysplasia (VACTERL/OAV) (22/148, 14%); EA with associated malformations including congenital heart defects, duodenal atresia, and diaphragmatic hernia without known associations or syndromes yet described (65/148, 44%). Altogether, the molecular diagnostic rate remains very low and may underlie frequent non-Mendelian genetic models.

Outcome of long gap esophageal atresia at 6 years: A prospective case control cohort study.

BACKGROUND DATA: EA is the most frequent congenital esophageal malformation. Long gap EA remains a therapeutic challenge for pediatric surgeons. A case case-control prospective study from a multi-institutional national French data base was performed to assess the outcome, at age of 1 and 6 years, of long gap esophageal atresia (EA) compared with non-long gap EA/tracheo-esophageal fistula (TEF). The secondary aim was to assess whether initial treatment (delayed primary anastomosis of native esophagus vs. esophageal replacement) influenced mortality and morbidity at ages 1 and 6 years. METHODS: A multicentric population-based prospective study was performed and included all patients who underwent EA surgery in France from January 1, 2008 to December 31, 2010. A comparative study was performed with non-long gap EA/TEF patients. Morbidity at birth, 1 year, and 6 years was assessed. RESULTS: Thirty-one patients with long gap EA were compared with 62 non-long gap EA/TEF patients. At age 1 year, the long gap EA group had longer parenteral nutrition support and longer hospital stay and were significantly more likely to have complications both early post-operatively and before age 1 year compared with the non-long gap EA/TEF group. At 6 years, digestive complications were more frequent in long gap compared to non-long gap EA/TEF patients. Tracheomalacia was the only respiratory complication that differed between the groups. Spine deformation was less frequent in the long gap group. There were no differences between conservative and replacement groups at ages 1 and 6 years except feeding difficulties that were more common in the native esophagus group. CONCLUSIONS: Long gap strongly influenced digestive morbidity at age 6 years.

Different Involvement of Vimentin during Invasion by Listeria monocytogenes at the Blood-Brain and the Blood-Cerebrospinal Fluid Barriers In Vitro.

The human central nervous system (CNS) is separated from the blood by distinct cellular barriers, including the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CFS) barrier (BCSFB). Whereas at the center of the BBB are the endothelial cells of the brain capillaries, the BCSFB is formed by the epithelium of the choroid plexus. Invasion of cells of either the BBB or the BCSFB is a potential first step during CNS entry by the Gram-positive bacterium Listeria monocytogenes (Lm). Lm possesses several virulence factors mediating host cell entry, such as the internalin protein family-including internalin (InlA), which binds E-cadherin (Ecad) on the surface of target cells, and internalin B (InlB)-interacting with the host cell receptor tyrosine kinase Met. A further family member is internalin (InlF), which targets the intermediate filament protein vimentin. Whereas InlF has been shown to play a role during brain invasion at the BBB, its function during infection at the BCSFB is not known. We use human brain microvascular endothelial cells (HBMEC) and human choroid plexus epithelial papilloma (HIBCPP) cells to investigate the roles of InlF and vimentin during CNS invasion by Lm. Whereas HBMEC present intracellular and surface vimentin (besides Met), HIBCPP cells do not express vimentin (except Met and Ecad). Treatment with the surface vimentin modulator withaferin A (WitA) inhibited invasion of Lm into HBMEC, but not HIBCPP cells. Invasion of Lm into HBMEC and HIBCPP cells is, however, independent of InlF, since a deletion mutant of Lm lacking InlF did not display reduced invasion rates.

Alternative splicing downstream of EMT enhances phenotypic plasticity and malignant behavior in colon cancer.

Phenotypic plasticity allows carcinoma cells to transiently acquire the quasi-mesenchymal features necessary to detach from the primary mass and proceed along the invasion-metastasis cascade. A broad spectrum of epigenetic mechanisms is likely to cause the epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial (MET) transitions necessary to allow local dissemination and distant metastasis. Here, we report on the role played by alternative splicing (AS) in eliciting phenotypic plasticity in epithelial malignancies with focus on colon cancer. By taking advantage of the coexistence of subpopulations of fully epithelial (EpCAMhi) and quasi-mesenchymal and highly metastatic (EpCAMlo) cells in conventional human cancer cell lines, we here show that the differential expression of ESRP1 and other RNA-binding proteins (RBPs) downstream of the EMT master regulator ZEB1 alters the AS pattern of a broad spectrum of targets including CD44 and NUMB, thus resulting in the generation of specific isoforms functionally associated with increased invasion and metastasis. Additional functional and clinical validation studies indicate that both the newly identified RBPs and the CD44s and NUMB2/4 splicing isoforms promote local invasion and distant metastasis and are associated with poor survival in colon cancer. The systematic elucidation of the spectrum of EMT-related RBPs and AS targets in epithelial cancers, apart from the insights in the mechanisms underlying phenotypic plasticity, will lead to the identification of novel and tumor-specific therapeutic targets.

CD44 expressed by myeloid cells promotes glioma invasion.

Glioblastoma multiforme (GBM) is one of the most common and malignant brain tumors in adulthood with a median survival of only 15 months. This poor prognosis is related to GBM's ability to extensively infiltrate the surrounding brain parenchyma resulting in diffuse spread of neoplastic cells in the brain, responsible for high rate of recurrence. CD44 (Cluster of Differentiation 44) is a transmembrane protein, overexpressed in multiple cancer types, including gliomas, and implicated in cell motility, proliferation and angiogenesis. Multiple studies have investigated the role of CD44 in GBM cells and have highlighted a link between tumor malignancy and CD44 expression. However up to date, little is known of the role of CD44 on cells from the tumor microenvironment (TME). Here, we have investigated a potential role of CD44 in the TME in regards to GBM invasiveness. Using an ex-vivo organotypic brain slice invasion assay, we show that absence of CD44 from the TME impairs the ability of glioma cells to invade the surrounding brain parenchyma. By deleting CD44 in the astrocytic, endothelial and myeloid compartments, we show that it is specifically CD44 expression in myeloid cells that is responsible for the observed phenotype. Combining in vivo studies in cell-specific knock-out mice and in vitro analyses on primary microglia we demonstrate that myeloid CD44 is implicated in Toll Like Receptor 2 signaling and is a major regulator of Matrix metalloproteinase 9 expression.

Direct interaction of TrkA/CD44v3 is essential for NGF-promoted aggressiveness of breast cancer cells.

BACKGROUND: CD44 is a multifunctional membrane glycoprotein. Through its heparan sulfate chain, CD44 presents growth factors to their receptors. We have shown that CD44 and Tropomyosin kinase A (TrkA) form a complex following nerve growth factor (NGF) induction. Our study aimed to understand how CD44 and TrkA interact and the consequences of inhibiting this interaction regarding the pro-tumoral effect of NGF in breast cancer. METHODS: After determining which CD44 isoforms (variants) are involved in forming the TrkA/CD44 complex using proximity ligation assays, we investigated the molecular determinants of this interaction. By molecular modeling, we isolated the amino acids involved and confirmed their involvement using mutations. A CD44v3 mimetic peptide was then synthesized to block the TrkA/CD44v3 interaction. The effects of this peptide on the growth, migration and invasion of xenografted triple-negative breast cancer cells were assessed. Finally, we investigated the correlations between the expression of the TrkA/CD44v3 complex in tumors and histo-pronostic parameters. RESULTS: We demonstrated that isoform v3 (CD44v3), but not v6, binds to TrkA in response to NGF stimulation. The final 10 amino acids of exon v3 and the TrkA H112 residue are necessary for the association of CD44v3 with TrkA. Functionally, the CD44v3 mimetic peptide impairs not only NGF-induced RhoA activation, clonogenicity, and migration/invasion of breast cancer cells in vitro but also tumor growth and metastasis in a xenograft mouse model. We also detected TrkA/CD44v3 only in cancerous cells, not in normal adjacent tissues. CONCLUSION: Collectively, our results suggest that blocking the CD44v3/TrkA interaction can be a new therapeutic option for triple-negative breast cancers.

Wnt signaling is boosted during intestinal regeneration by a CD44-positive feedback loop.

Enhancement of Wnt signaling is fundamental for stem cell function during intestinal regeneration. Molecular modules control Wnt activity by regulating signal transduction. CD44 is such a positive regulator and a Wnt target gene. While highly expressed in intestinal crypts and used as a stem cell marker, its role during intestinal homeostasis and regeneration remains unknown. Here we propose a CD44 positive-feedback loop that boosts Wnt signal transduction, thus impacting intestinal regeneration. Excision of Cd44 in Cd44fl/fl;VillinCreERT2 mice reduced Wnt target gene expression in intestinal crypts and affected stem cell functionality in organoids. Although the integrity of the intestinal epithelium was conserved in mice lacking CD44, they were hypersensitive to dextran sulfate sodium, and showed more severe inflammation and delayed regeneration. We localized the molecular function of CD44 at the Wnt signalosome, and identified novel DVL/CD44 and AXIN/CD44 complexes. CD44 thus promotes optimal Wnt signaling during intestinal regeneration.

Santulli Procedure Revisited in Congenital Intestinal Malformations and Postnatal Intestinal Injuries: Preliminary Report of Experience.

In our experience, the Santulli procedure (SP) can improve bowel recovery in congenital intestinal malformations, necrotizing enterocolitis (NEC), and bowel perforation. All cases managed at our institution using SP between 2012 and 2017 were included in this study. Forty-one patients underwent SP (median age: 39 (0-335) days, median weight: 2987 (1400-8100) g) for intestinal atresia (51%, two gastroschisis), NEC (29%), midgut volvulus (10%), Hirschsprung's disease (5%), or bowel perforation (5%), with at least one intestinal suture below the Santulli in 10% of cases. The SP was performed as a primary procedure (57%) or as a double-ileostomy reversal. Anal-stool passing occurred within a median of 9 (2-36) days for 95% of patients, regardless of the diversion level or the underlying disease. All three patients requiring repeated surgery for Santulli dysfunction had presented with stoma prolapse (p < 0.01). Stoma closure was performed after a median of 45 (14-270) days allowing efficient transit after a median of 2 (1-6) days. After a median follow-up of 2.9 (0.7-7.2) years, two patients died (cardiopathy and brain hemorrhage), full oral intake had been achieved in 90% of patients, and all survivors had normal bowel movement. Whether used as primary or secondary surgery, the SP allows rapid recovery of intestinal motility and function.

Feeding disorders in children with oesophageal atresia: a cross-sectional study.

INTRODUCTION: With advances in surgical and neonatal care, the survival of patients with oesophageal atresia (OA) has improved over time. Whereas a number of OA-related conditions (delayed primary anastomosis, anastomotic stricture and oesophageal dysmotility) may have an impact on feeding development and although children with OA experience several oral aversive events, paediatric feeding disorders (PFD) remain poorly described in this population. The primary aim of our study was to describe PFD in children born with OA, using a standardised scale. The secondary aim was to determine conditions associated with PFD. METHODS: The Feeding Disorders in Children with Oesophageal Atresia Study is a national cohort study based on the OA registry from the French National Network. Parents of children born with OA between 2013 and 2016 in one of the 22 participating centres were asked to complete the French version of the Montreal Children's Hospital Feeding Scale. RESULTS: Of the 248 eligible children, 145 children, with a median age of 2.3 years (Q1-Q3 1.8-2.9, min-max 1.1-4.0 years), were included. Sixty-one children (42%) developed PFD; 13% were tube-fed (n=19). Almost 40% of children with PFD failed to thrive (n=23). The presence of chronic respiratory symptoms was associated with the development of PFD. Ten children with PFD (16%) had no other condition or OA-related complication. CONCLUSION: PFD are common in children with OA, and there is no typical profile of patients at risk of PFD. Therefore, all children with OA require a systematic screening for PFD that could improve the care and outcomes of patients, especially in terms of growth.

Predicting Factors of Protracted Intestinal Failure in Children with Gastroschisis.

OBJECTIVE: To identify prenatal and neonatal predictors of short bowel syndrome-related intestinal failure (SBS-IF) in gastroschisis. STUDY DESIGN: This retrospective study included all patients with gastroschisis born between 2000 and 2017 who were enrolled in our home parenteral nutrition program, and all patients with gastroschisis born in our institution who survived 2 weeks, during the same time period. Prenatal ultrasound features, neonatal status, anatomic features, oral feeding, and parenteral nutrition dependency were analyzed. RESULTS: Among 180 patients, 35 required long-term parenteral nutrition (SBS-IF group) and 145 acquired full oral feeding within 6 months (oral feeding group). The mean follow-up was 7.9 years (IQR, 1.6-17.5 years) and 5.0 years (IQR, 0.1-18.2 years), respectively. Both bowel matting (OR, 14.23; 1.07-16.7; P = .039) and secondarily diagnosed atresia or stenosis (OR, 17.78; 3.13-100.98; P = .001) were independent postnatal predictors of SBS-IF. Eighteen children (51% of the SBS-IF group) were still dependent on artificial nutrition at the last follow-up. patients with SBS-IF who achieved full oral feeding had a median residual small-bowel length of 74 cm (IQR, 51-160 cm) vs 44 cm (IQR, 10-105 cm) for those still dependent on artificial nutrition (P = .02). An initial residual small bowel length of more than 50 cm was the best predictive cut-off for nutritional autonomy, with a sensitivity of 67% and a specificity of 100%. CONCLUSIONS: Bowel matting, complex gastroschisis, and secondary intestinal obstruction were associated with SBS-IF in gastroschisis. For patients with SBS-IF, a small bowel length of more than 50 cm was predictive of secondary nutritional autonomy.