Favorable outcomes in high-risk congenital pulmonary airway malformations treated with multiple courses of maternal betamethasone.

BACKGROUND/PURPOSE: Congenital pulmonary airway malformations (CPAMs) are rare congenital lung lesions often diagnosed by prenatal ultrasound. High-risk cases can result in hydrops and prenatal or postnatal demise. Antenatal betamethasone has resulted in improved survival but it is unclear how to manage patients who do not respond to a single course. METHODS: We present a bi-institutional retrospective review of patients treated with multiple courses of prenatal steroids for high-risk CPAMs between 2007 and 2013. RESULTS: Nine patients met inclusion criteria. All but one either had an increased CPAM volume ratio (CVR) or number of fluid-containing compartments involved after a single course of antenatal betamethasone, prompting additional courses. Four patients stabilized, three improved and two progressed after the second course. The two cases with disease progression underwent an in utero resection. There were one in utero fetal demise and two deaths within the delivery room. Both fetuses that underwent a fetal resection died. All but one mother who delivered a viable fetus had complications of pregnancy. CONCLUSIONS: Multiple courses of antenatal betamethasone for high-risk fetal CPAMs often result in favorable short-term outcomes without the need for open fetal resection. Pregnancy complications are common and women within this cohort should be monitored closely.

Decreased risk of graft failure with maternal liver transplantation in patients with biliary atresia.

The presence of maternal cells in offspring may promote tolerance to noninherited maternal antigens (NIMAs). Children with biliary atresia (BA) have increased maternal cells in their livers, which may impact tolerance. We hypothesized that patients with BA would have improved outcomes when receiving a maternal liver. We reviewed all pediatric liver transplants recorded in the SRTR database from 1996 to 2010 and compared BA and non-BA recipients of maternal livers with recipients of paternal livers for the incidences of graft failure and retransplantation. Rejection episodes after parental liver transplantation were examined for patients transplanted at our institution. BA patients receiving a maternal graft had lower rates of graft failure compared to those receiving a paternal graft (3.7% vs. 10.5%, p = 0.02) and, consequently, fewer episodes of retransplantation (2.7% vs. 7.5%, p = 0.04). These differences were not seen among non-BA patients or among BA patients who received female deceased donor grafts. In patients transplanted at our institution, paternal liver transplantation was associated with an increased incidence of refractory rejection compared to maternal liver transplantation only in BA. Our data support the concept that maternal cells in BA recipients promote tolerance to NIMAs and may be important in counseling BA patients who require liver transplantation.

Human mesenchymal stem cells persist, demonstrate site-specific multipotential differentiation, and are present in sites of wound healing and tissue regeneration after transplantation into fetal sheep.

Prenatal transplantation of stem cells is an exciting frontier for the treatment of many congenital diseases. The fetus may be an ideal recipient for stem cells, as it is immunologically immature and has rapidly proliferating cellular compartments that may support the engraftment of transplanted cells. Mesenchymal stem cells (MSC), given their ability to differentiate into multiple cell types, could potentially be used to treat diseases such as osteogenesis imperfecta, muscular dystrophy, and other mesenchymal disorders that can be diagnosed in utero. We have shown, using a human-sheep in utero xenotransplantation model, that human MSC have the ability to engraft, undergo site-specific differentiation into multiple cell types, and survive for more than 1 year in fetal lamb recipients. In addition, in this model MSC-derived cells appear to be present in increased numbers in wounded or regenerating tissues. This observation warrants further studies of the biology of MSCs following systemic or site-directed transplantation.

The management of prenatally diagnosed choledochal cysts.

BACKGROUND: Although congenital biliary tree abnormalities are uncommon in the United States, more are being diagnosed antenatally with improved imaging techniques. METHODS: To determine the prognosis of prenatally diagnosed biliary disease, the authors reviewed the treatment of 3 children who had biliary cystic lesions found during routine prenatal ultrasonography. RESULTS: All 3 children were born at term. They had elevated bilirubin levels, and postnatal ultrasound scans confirmed the presence of a biliary cystic mass. They underwent exploration within 2 weeks of life. At operation, 2 children were found to have biliary atresia with a cystic biliary lesion. They underwent Kasai procedures and are doing well at 5 and 9 months of age. The third child was found to have a type I choledochal cyst and malrotation at exploration. He underwent cystectomy with Roux-en-Y hepaticojejunostomy and a Ladd's procedure and is doing well at 3 years of age. CONCLUSIONS: Prenatally diagnosed biliary cysts represent a different spectrum of disease than those diagnosed later in life. The sequelae of biliary disease start before birth, and early operation may be necessary to achieve a good outcome. Because it is impossible to distinguish between choledochal cysts and biliary atresia on antenatal ultrasound scan or magnetic resonance imaging, children with presumed choledochal cysts should undergo early exploration to rule out potential biliary atresia. Excellent outcome is possible with early operation in the absence of severe associated anomalies.

A fetal lung lesion consisting of bronchogenic cyst, bronchopulmonary sequestration, and congenital cystic adenomatoid malformation: the missing link?

A fetus was found to have a large left thoracic cyst on routine prenatal ultrasound at 23 weeks of gestation. This lesion caused compression of the normal left lung tissue and contralateral mediastinal shift. At 23 weeks of gestation the cyst was percutaneously aspirated without subsequent reaccumulation of fluid. Serial ultrasounds showed decrease in the size of the cyst. The clinical diagnosis of congenital cystic adenomatoid malformation was made. At birth, the child had no respiratory distress, and a CT scan confirmed the finding of a fluid-filled cyst in the left chest. At the time of resection, a nonaerated extralobar bronchopulmonary sequestration (with a systemic arterial blood supply and separate pleural investment) was found. The dominant cyst had ciliated respiratory epithelium with cartilage, indicative of a bronchogenic cyst, and the remainder of the specimen had the histologic hallmarks of a congenital cystic adenomatoid malformation. The coexistence of three separate anomalies in one lesion suggests a common embryological link for these malformations.

Multilineage differentiation of human MSC after in utero transplantation.

Prenatal transplantation of stem cells is an exciting frontier for the treatment of many congenital diseases. The fetus may be an ideal recipient for stem cells, as it is immunologically immature and has rapidly proliferating cellular compartments that may support the engraftment of transplanted cells. Mesenchymal stem cells (MSC), given their ability to differentiate among multiple lineages, could potentially be used to treat diseases such as osteogenesis imperfecta, muscular dystrophy, and a variety of others that can be diagnosed in utero. We have shown, using a human-sheep in utero xenotransplantation model, that human MSC have the ability to engraft, differentiate into many tissue types, and survive for over 1 year in fetal lamb recipients. This observation warrants further studies of the behavior of MSC following systemic or site-directed transplantation.

Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep.

Mesenchymal stem cells are multipotent cells that can be isolated from adult bone marrow and can be induced in vitro and in vivo to differentiate into a variety of mesenchymal tissues, including bone, cartilage, tendon, fat, bone marrow stroma, and muscle. Despite their potential clinical utility for cellular and gene therapy, the fate of mesenchymal stem cells after systemic administration is mostly unknown. To address this, we transplanted a well-characterized human mesenchymal stem cell population into fetal sheep early in gestation, before and after the expected development of immunologic competence. In this xenogeneic system, human mesenchymal stem cells engrafted and persisted in multiple tissues for as long as 13 months after transplantation. Transplanted human cells underwent site-specific differentiation into chondrocytes, adipocytes, myocytes and cardiomyocytes, bone marrow stromal cells and thymic stroma. Unexpectedly, there was long-term engraftment even when cells were transplanted after the expected development of immunocompetence. Thus, mesenchymal stem cells maintain their multipotential capacity after transplantation, and seem to have unique immunologic characteristics that allow persistence in a xenogeneic environment. Our data support the possibility of the transplantability of mesenchymal stem cells and their potential utility in tissue engineering, and cellular and gene therapy applications.