Hester F. Shieh

Posterior tracheopexy for severe tracheomalacia

PURPOSE In severe tracheomalacia, aortopexy addresses anterior vascular compression, but does not directly address posterior membranous tracheal intrusion. We review patient outcomes of posterior tracheopexy for tracheomalacia with posterior intrusion to determine if there were resolution of clinical symptoms and bronchoscopic evidence of improvement in airway collapse. METHODS All patients who underwent posterior tracheopexy from October 2012 to March 2016 were retrospectively reviewed. Clinical symptoms, tracheomalacia scores based on standardized dynamic airway evaluation by anatomical region, and persistent airway intrusion were collected. Data were analyzed by Wald and Wilcoxon signed-ranks tests. RESULTS 98 patients (51% male) underwent posterior tracheopexy at a median age of 15months (IQR 6-33months). Median follow-up was 5months (range 0.25-36months). There were statistically significant improvements in clinical symptoms postoperatively, including cough, noisy breathing, prolonged and recurrent respiratory infections, transient respiratory distress requiring positive pressure, oxygen dependence, blue spells, and apparent life-threatening events (p<0.001), as well as ventilator dependence (p=0.04). Tracheomalacia scores on bronchoscopy improved significantly in all regions of the trachea and bronchi (p<0.001). 9.2% had persistent airway intrusion requiring reoperation, usually with aortopexy. CONCLUSIONS Posterior tracheopexy is effective in treating severe tracheomalacia with significant improvements in clinical symptoms and degree of airway collapse on bronchoscopy. LEVEL OF EVIDENCE Level III, treatment study.

Does the ex utero intrapartum treatment to extracorporeal membrane oxygenation procedure change morbidity outcomes for high-risk congenital diaphragmatic hernia survivors?

PURPOSE In high-risk congenital diaphragmatic hernia (CDH), significant barotrauma or death can occur before extracorporeal membrane oxygenation (ECMO) can be initiated. We previously examined ex utero intrapartum treatment (EXIT)-to-ECMO in our most severe CDH patients, but demonstrated no survival advantage. We now report morbidity outcomes in survivors of this high-risk cohort to determine whether EXIT-to-ECMO conferred any benefit. METHODS All CDH survivors with <15% predicted lung volume (PPLV) from September 1999 to December 2010 were included. We recorded prenatal imaging, defect size, and pulmonary, nutritional, cardiac, and neurodevelopmental outcomes. RESULTS Seventeen survivors (8 EXIT-to-ECMO, 9 non-EXIT) had an average PPLV of 11.7%. Eight of 9 non-EXIT received ECMO within 2days. There were no significant defect size differences between groups, mostly left-sided (13/17) and type D (12/17). Average follow-up was 6.7years (0-13years). There were no statistically significant differences in outcomes, including supplemental oxygen, diuretics, gastrostomy, weight-for-age Z scores, fundoplication, pulmonary hypertension, stroke or intracranial hemorrhage rate, CDH recurrence, and reoperation. No survivor in our cohort was neurologically devastated. All had mild motor and/or speech delay, which improved in most. CONCLUSIONS In this pilot series of severe CDH survivors, EXIT-to-ECMO confers neither significant survival nor long-term morbidity benefit. LEVEL OF EVIDENCE Level III treatment study.

Transamniotic stem cell therapy (TRASCET) in a leporine model of gastroschisis.

BACKGROUND/PURPOSE Transamniotic stem cell therapy (TRASCET) with amniotic fluid mesenchymal stem cells (afMSCs) has been shown to mitigate bowel damage in a rodent model of gastroschisis. As a prerequisite to clinical translation, we sought to study TRASCET in a larger animal model. METHODS New Zealand rabbit fetuses (n=64) with surgically created gastroschisis were divided into three groups. One group (untreated) had no further manipulations. Two groups received volume-matched intraamniotic injections of either saline or a suspension of afMSCs. Nonmanipulated fetuses served as controls. Histomorphologic measurements of intestinal damage, along with biochemical profiling of inflammation markers, were performed at term. Statistical comparisons were by Fishers exact test, ANOVA and the Wald test (P<0.05). RESULTS Overall survival was 62.5%. Segmental and total intestinal wall thicknesses were significantly decreased in the afMSC group compared with the untreated and saline groups (all P<0.001), with no significant differences between untreated and saline groups (P=0.24 to 1.00, depending on layer). Muscularis and serosal layers were significantly thicker in the afMSC group than in normal controls (P=0.045 and P<0.001, respectively). CONCLUSIONS Concentrated intraamniotic injection of afMSC lessens, yet does not prevent, intestinal damage in a leporine model of gastroschisis. TRASCET may become a valuable strategy in the management of gastroschisis. LEVEL OF EVIDENCE N/A - animal/experimental studies.

Donor mesenchymal stem cells home to maternal wounds after transamniotic stem cell therapy (TRASCET) in a rodent model.

PURPOSE Transamniotic stem cell therapy (TRASCET) with amniotic fluid-derived MSCs (afMSCs) has emerged experimentally as a practical treatment strategy for congenital anomalies. In this study, we sought to determine whether afMSCs migrate to the mother following TRASCET. METHODS Pregnant rat dams were divided into three groups. Two groups received volume-matched injections into all amniotic cavities of either a suspension of afMSCs labeled with a luciferase reporter gene or the luciferase protein alone. In a third group, a suspension of labeled cells was aliquoted onto the serosal surface of the uterus. Maternal samples from the laparotomy scar (fascia and skin separately), bone marrow, and peripheral blood were procured, along with placenta and umbilical cord. Specimens were screened for luminescence via microplate luminometry. RESULTS Luminescence was detected in 60% (9/15) of the fascial scars from the group receiving intraamniotic injection of afMSCs, but in none of the other groups (P<0.001). There was a direct correlation between the presence of donor cells in the placenta and their presence in maternal fascia (Wald test=10.2; P=0.001). CONCLUSIONS Amniotic mesenchymal stem cells migrate to maternal sites of injury after intraamniotic injection. Maternal homing of donor cells must be considered in the setting of transamniotic stem cell therapy. LEVEL OF EVIDENCE N/A (animal and laboratory study).

Posterior Tracheopexy for Severe Tracheomalacia Associated with Esophageal Atresia (EA): Primary Treatment at the Time of Initial EA Repair versus Secondary Treatment

Purpose We review outcomes of posterior tracheopexy for tracheomalacia in esophageal atresia (EA) patients, comparing primary treatment at the time of initial EA repair versus secondary treatment. Methods All EA patients who underwent posterior tracheopexy from October 2012 to September 2016 were retrospectively reviewed. Clinical symptoms, tracheomalacia scores, and persistent airway intrusion were collected. Indication for posterior tracheopexy was the presence of clinical symptoms, in combination with severe tracheomalacia as identified on bronchoscopic evaluation, typically defined as coaptation in one or more regions of the trachea. Secondary cases were usually those with chronic respiratory symptoms who underwent bronchoscopic evaluation, whereas primary cases were those found to have severe tracheomalacia on routine preoperative dynamic tracheobronchoscopy at the time of initial EA repair. Results A total of 118 patients underwent posterior tracheopexy: 18 (15%) primary versus 100 (85%) secondary cases. Median (interquartile range) age was 2 months (1–4 months) for primary (22% type C) and 18 months (8–40 months) for secondary (87% type C) cases (p < 0.001). There were statistically significant improvements in most clinical symptoms postoperatively for primary and secondary cases, with no significant differences in any postoperative symptoms between the two groups (p > 0.1). Total tracheomalacia scores improved significantly in primary (p = 0.013) and secondary (p < 0.001) cases. Multivariable Cox regression analysis indicated no differences in persistent airway intrusion requiring reoperation between primary and secondary tracheopexy adjusting for imbalances in age and EA type (p = 0.67). Conclusion Posterior tracheopexy is effective in treating severe tracheomalacia with significant improvements in clinical symptoms and degree of airway collapse on bronchoscopy. With no significant differences in outcomes between primary and secondary treatment, posterior tracheopexy should be selectively considered at the time of initial EA repair.

Three-dimensional printing of external airway splints for tracheomalacia

Three-dimensional (3D) printing technology has been used to create personalized medical devices. There is growing interest in the use of 3D-printed biomaterials to create four-dimensional (4D) structure, such that the 3D-printed devices are engineered to adapt and change with tissue growth based on biomechanical and degradation properties over a specified time period (1).

Fetal bone marrow homing of donor mesenchymal stem cells after transamniotic stem cell therapy (TRASCET)

PURPOSE Donor cell engraftment patterns following transamniotic stem cell therapy (TRASCET) with amniotic fluid mesenchymal stem cells (afMSCs) are incompatible with solely direct amniotic seeding. We sought to determine whether fetal bone marrow is a component of such engraftment and to examine the chronology of afMSC placental trafficking. METHODS Two groups of Sprague-Dawley rat fetuses received volume-matched intraamniotic injections on gestational day 17 (E17; term E22): either afMSCs labeled with a luciferase reporter gene or luciferase protein alone. Placental samples were procured at daily time points thereafter until term. Fetal bone marrow was obtained at term only owing to size constraints. Specimens were screened for luminescence via microplate luminometry. RESULTS Donor afMSCs were identified in the bone marrow and placenta of fetuses receiving labeled afMSCs, but not in those receiving luciferase alone (P<0.001). Luminescence was significantly higher in placentas at E18 compared to E19 (P<0.001), E20 (P=0.007), and E21 (P=0.004), with no difference with E22/term (P=0.97). CONCLUSIONS Donor mesenchymal stem cells home to the fetal bone marrow after intraamniotic injection. The chronology of placental trafficking is suggestive of controlled cell routing rather than plain cell clearance. Fetal bone marrow engraftment of donor cells significantly expands potential applications of transamniotic stem cell therapy.

Descending Aortopexy and Posterior Tracheopexy for Severe Tracheomalacia and Left Mainstem Bronchomalacia

Posterior descending aortopexy can relieve posterior intrusion of the left mainstem bronchus that may limit the effectiveness of posterior tracheobronchopexy. We review outcomes of patients undergoing both descending aortopexy and posterior tracheopexy for severe tracheobronchomalacia with posterior intrusion and left mainstem compression to determine if there were resolution of clinical symptoms and bronchoscopic evidence of improvement in airway collapse. All patients who underwent both descending aortopexy and posterior tracheopexy from October 2012 to October 2016 were retrospectively reviewed. Clinical symptoms, tracheomalacia scores based on standardized dynamic airway evaluation by anatomical region, and persistent airway intrusion requiring reoperation were collected. Data were analyzed by Wald and Wilcoxon signed-rank tests. Thirty-two patients underwent descending aortopexy and posterior tracheopexy at median age of 18 months (interquartile range 6-40 months). Median follow-up was 3 months (interquartile range 1-7 months). There were statistically significant improvements in clinical symptoms postoperatively, including cough, noisy breathing, prolonged and recurrent respiratory infections, ventilator dependence, blue spells, and brief resolved unexplained events (all P < 0.001), as well as exercise intolerance (P = 0.033), transient respiratory distress requiring positive pressure (P = 0.003), and oxygen dependence (P = 0.007). Total tracheomalacia scores improved significantly (P < 0.001), with significant segmental improvements in the middle (P = 0.003) and lower (P < 0.001) trachea, and right (P = 0.011) and left (P < 0.001) mainstem bronchi. Two patients (6%) had persistent airway intrusion requiring reoperation with anterior aortopexy or tracheopexy. Descending aortopexy and posterior tracheopexy are effective in treating severe tracheobronchomalacia and left mainstem intrusion with significant improvements in clinical symptoms and degree of airway collapse on bronchoscopy.

Donor mesenchymal stem cell linetics after transamniotic stem cell therapy (TRASCET) for experimental spina bifida

PURPOSE We sought to examine donor mesenchymal stem cell (MSC) kinetics after transamniotic stem cell therapy (TRASCET) in experimental spina bifida. METHODS Pregnant Sprague-Dawley dams exposed to retinoic acid for the induction of fetal neural tube defects received volume-matched intra-amniotic injections on gestational day 17 (E17; term=E22): either amniotic fluid MSCs (afMSCs) labeled with a luciferase reporter gene (n=78), or luciferase protein alone (n=66). Samples from twelve organ systems from each surviving fetus with spina bifida (total n=60) were screened via microplate luminometry at term. RESULTS Donor afMSCs were identified exclusively in the placenta, umbilical cord, spleen, bone marrow, hip bones, defect, and brain. Luminometry was negative in control fetuses receiving luciferase alone (p<0.001). Signal intensity in relative light units (RLUs) was moderately correlated between the defect and the hip bones (rho=0.38, p=0.048), and between the placenta and the brain (rho=0.40, p=0.038). CONCLUSIONS Amniotic mesenchymal stem cells engraft to specific sites after concentrated intra-amniotic injection in the setting of spina bifida. A hematogenous route encompassing the bone marrow as well as distant central nervous system homing are fundamental constituents of cell trafficking. These findings must be considered during eventual patient selection for transamniotic stem cell therapy in the prenatal management of spina bifida.

Percent predicted lung volume changes on fetal magnetic resonance imaging throughout gestation in congenital diaphragmatic hernia

PURPOSE Percent predicted lung volume (PPLV)<15% on fetal MRI predicts high-risk CDH. Potential changes in PPLV throughout gestation and impact on risk stratification are unknown. We reviewed CDH patients with serial fetal MRIs to follow PPLV and determine correlation with postnatal outcomes. METHODS CDH patients with serial fetal MRIs from 2005 to 2015 were included. We recorded prenatal MRI gestational age (GA) and PPLV, postnatal ECMO use, and survival. Data were analyzed by logistic regression and Fishers exact test. RESULTS 57 patients had 127 fetal MRI studies. PPLV decreased from mean 25.4% to 19.6% between GA 22.1 and 32.6weeks. A steeper decline in PPLV, regardless of final PPLV, was independently predictive of higher ECMO use (p=0.046) and death (p=0.045). All patients with first PPLV<15% remained high-risk with poor outcomes. Of those with first PPLV>15%, 31% dropped below 15%, having similar ECMO use as the high-risk cohort, but trending toward greater survival (p=0.09). Those with first and final PPLV>15% had significantly less ECMO use (p=0.015) and greater survival (p<0.001) than the high-risk cohort. CONCLUSIONS On average, PPLV decreases throughout gestation in fetuses with CDH. Serial MRI is recommended for those with initial PPLV>15%, as clinical outcomes tend to mirror the lowest PPLV. TYPE OF STUDY Treatment study LEVEL OF EVIDENCE: III.