Needle fetal thoracoscopy: a technique to assist with ultrasound-guided placement of challenging thoracoamniotic shunts.

INTRODUCTION: Fetal thoracoamniotic shunts are common lifesaving interventions but frequently require replacement. Needle fetal thoracoscopy is a technique that uses standard thoracoamniotic shunt introducer sheaths to permit direct visualization and even instrument manipulation during shunt deployment to facilitate optimal positioning and primary shunt function in the most challenging cases. CASE PRESENTATION: In this study, five patients who underwent needle fetal thoracoscopy-assisted thoracoamniotic shunt placement were reviewed. Three patients with large, macrocystic congenital pulmonary airway malformations (CPAM) with evidence of worsening mediastinal shift and/or hydrops and two patients with large chylothorax with fetal hydrops were treated. Four cases had previous shunts that failed due to poor sonographic visualization during initial placement, cyst septations, shunt obstruction or dislodgment. Needle fetal thoracoscopy was used to disrupt cyst walls and septations, clear hematoma, and confirm optimal initial position of the shunt. In this series, one severe CPAM patient with short cervix developed preterm labor postoperatively resulting in neonatal demise. The remaining four patients experienced resolution of hydrops and progressed to successful delivery with excellent neonatal outcomes. CONCLUSION: Needle fetal thoracoscopy is a procedure that may be selectively deployed in challenging thoracoamniotic shunt cases impacted by recurrent failure, poor sonographic windows, and challenging fetal positioning.

Ex-Utero Intrapartum Treatment-to-Airway for Obstructing Fetal Neck Masses: A Singular Methodology for Monochorionic and Dichorionic Twin Pregnancies.

Fetal airway obstruction in one twin of a diamniotic pregnancy presents unique challenges. Very few cases of ex-utero-intrapartum-treatment (EXIT) procedures for twin pregnancy have been reported and only in dichorionic pregnancies. We report a singular methodology for EXIT-to-airway procedures in two pregnancies involving monochorionic and dichorionic twins. Two cases of EXIT-to-airway in twin pregnancies were performed in 2018 and 2019 at a regional fetal treatment center. Case 1 involved a giant cervical teratoma in a monochorionic-diamniotic twin pregnancy with preterm labor at 29 weeks. Case 2 involved a dichorionic-diamniotic pregnancy with a large cervical lymphatic malformation with preterm labor at 36 weeks. In each case, the polyhydramnios caused the affected twin's amniotic sac to be the presenting sac for the surgical approach. Bronchoscopy and successful intubation was completed after 22 and 10 minutes of uteroplacental bypass, respectively. The bystander twins were delivered second without intubation and resuscitated without perinatal distress. EXIT-to-airway appears to be a reasonable option for twins including monochorionic pregnancies, via delivery of the affected twin first followed by delivery of the bystander twin. Thoughtful preparation and counseling by an experienced multidisciplinary team permits an EXIT-to-airway approach for twin pregnancies even in an emergent setting.

Nonparasitic Splenic Cysts in Children: Outcomes after Sclerotherapy or Surgical Resection as Initial Management.

Management of splenic cysts in children remains undefined. Sclerotherapy is an innovative, less invasive treatment. This study examined the safety and preliminary effectiveness of sclerotherapy for splenic cysts in children compared with those of surgical treatment. A retrospective review of pediatric patients treated for nonparasitic splenic cysts from 2007 to 2021 was performed at a single institution. Posttreatment outcomes for patients who underwent either expectant management, sclerotherapy, or surgery were reviewed. Thirty patients aged between 0 and 18 years met the inclusion criteria. Cysts in 3 of 8 patients who underwent sclerotherapy were either unresolved or recurred. Patients who underwent sclerotherapy and required surgery for residual symptomatic cyst had an initial cyst diameter of >8 cm. Symptoms resolved in 5 of 8 patients who underwent sclerotherapy, with a significantly reduced cyst size compared with that in patients with continued symptoms who underwent sclerotherapy (61.4% vs 7.0%, P = .01). Sclerotherapy is an effective treatment for splenic cysts, particularly those measuring <8 cm. However, surgical excision may be preferable for large cysts.

CD4 and IL-2 mediated NK cell responses after COVID-19 infection and mRNA vaccination in adults.

A detailed understanding of protective immunity against SARS-CoV-2 is incredibly important in fighting the pandemic. Central to protective immunity is the ability of the immune system to recall previous exposures. Although antibody and T cell immunity have gained considerable attention, the contribution of the NK cell compartment to immune recall and protection from SARS-CoV-2 has not been explored. In this study, we investigate the NK cell responses to stimulation with SARS-CoV-2 in previously exposed and non-exposed individuals. We show that NK cells demonstrate an enhanced CD4+ T cell dependent response when re-exposed to SARS-CoV-2 antigen. The enhanced response is dependent on T cells and correlates with the number of SARS-CoV-2 specific CD4 T cells. We find that IL-2 is a critical mediator of NK cell function. These findings suggest that NK cells contribute to the protective responses against SARS-CoV-2 through a cooperation with antigen-specific CD4 T cells and have significant implications on our understanding of protective immunity in SARS-CoV-2.

The interplay between prenatal liver growth and lung development in congenital diaphragmatic hernia.

Objective: Liver herniation is a known risk factor for increased severity in CDH and is associated with clinically significant pulmonary hypoplasia and pulmonary hypertension. Better studies are needed to understand the growth of the herniated liver compared to the liver that remains in the abdomen and how this liver growth then affects lung development. Serial hi-resolution fetal MRI enables characterization of liver growth throughout gestation and examination of macroscopic features that may regulate liver growth. Here, we hypothesized that the nature of liver herniation affects liver growth and, in turn, affects lung growth. Methods: Clinical data were retrospectively collected from consecutive cases of prenatally diagnosed isolated left-sided or right-sided CDH from June 2006 to August 2021. Only those cases with MRI lung volumetry for both mid-gestation and late-gestation time points were recruited for analysis. Cases with fetal chromosomal abnormalities and other major structural abnormalities were excluded. Fractional liver volume and liver growth was indexed to estimated fetal weight and compared to lung growth. Results: Data was collected from 28 fetuses with a left liver-down CDH (LLD), 37 left liver-up CDH (LLU) and 9 right liver-up CDH (RLU). Overall, RLU fetuses had greater overall and fractional (intra-thoracic vs. intra-abdominal) liver growth when compared to LLD and LLU fetuses. Additionally, intra-thoracic liver growth was consistently slower than intra-abdominal liver growth for either right- or left-sided CDH. When the liver was not herniated, a positive correlation was seen between liver growth and lung growth. However, when the liver was herniated above the diaphragm, this positive correlation was lost. Conclusion: Right-sided CDH fetuses exhibit greater liver growth compared to left-sided CDH. Liver herniation disrupts the normal positive correlation between liver and lung growth that is seen when the liver is entirely within the abdomen.

Mentorship in pediatric surgery: A need for structure?

INTRODUCTION: Mentorship in surgical training is critical but differs greatly from the early apprenticeship model and often spans generations. This study evaluates the current state of and desire for structured mentorship in pediatric surgical training from the perspective of program directors (PDs) and trainees. METHODS: A survey addressing demographics, presence of or desire for structured mentorship, and proposed mentoring topics was emailed to pediatric surgery PDs (n = 58) and trainees completing fellowship in 2018-2020 (n = 72). RESULTS: The response rate was 38.5%. 50% of trainees were female versus 15% of PDs (p = 0.02). 19% of trainees reported having a structured mentorship program versus 26% of PDs (p = 0.72). The majority, 83%, of trainees felt a structured mentorship program is warranted versus 40% of PDs (p = 0.002). There were differing opinions between trainees and PDs regarding important components of a mentoring program. Trainees felt the following were more important: transition to practice, job negotiation, CV review, financial planning and performance review. PDs felt the following were more important: quality improvement projects and work/life balance. Both agreed academic development and job search were important. CONCLUSIONS: The majority of pediatric surgery trainees desire structured mentorship programs; however, few institutions have them. Training programs and program directors warrant a response to this gap. LEVEL OF EVIDENCE: IV.

The management of pediatric renovascular hypertension: a single center experience and review of the literature.

INTRODUCTION: Renal artery occlusive disease is poorly characterized in children; treatments include medications, endovascular techniques, and surgery. We aimed to describe the course of renovascular hypertension (RVH), its treatments and outcomes. METHODS: We performed literature review and retrospective review (1993-2014) of children with renovascular hypertension at our institution. Response to treatment was defined by National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents at most-recent follow-up. RESULTS: We identified 39 patients with RVH. 54% (n=21) were male, with mean age of 6.93 ± 5.27 years. Most underwent endovascular treatment (n=17), with medication alone (n=12) and surgery (n=10) less commonly utilized. Endovascular treatment resulted in 18% cure, 65% improvement and 18% failure; surgery resulted in 30% cure, 50% improvement and 20% failure. Medication alone resulted in 0% cure, 75% improvement and 25% failure. 24% with endovascular treatment required secondary endovascular intervention; 18% required secondary surgery. 20% of patients who underwent initial surgery required reoperation for re-stenosis. Mean follow-up was 52.2 ± 58.4 months. CONCLUSIONS: RVH treatment in children includes medications, surgical or endovascular approaches, with all resulting in combined 79% improvement in or cure rates. A multidisciplinary approach and individualized patient management are critical to optimize outcomes. TYPE OF STUDY: Retrospective comparative study LEVEL OF EVIDENCE: Level III.

Extrinsic allospecific signals of hematopoietic origin dictate iNKT cell lineage-fate decisions during development.

Invariant NKT (iNKT) cells are critical to the maintenance of tolerance toward alloantigens encountered during postnatal life pointing to the existence of a process for self-education. However, the impact of developmentally encountered alloantigens in shaping the phenotype and function of iNKT cells has not been described. To better understand this process, the current report examined naïve iNKT cells as they matured in an allogeneic environment. Following the prenatal transfer of fetal hematopoietic cells between age-matched allogeneic murine fetuses, cell-extrinsic signals appeared to dictate allospecific patterns of Ly49 receptor expression and lineage diversity in developing iNKT cells. Regulation for this process arose from cells of hematopoietic origin requiring only rare exposure to facilitate broad changes in developing iNKT cells. These findings highlight surprisingly asymmetric allospecific alterations in iNKT cells as they develop and mature in an allogeneic environment and establish a new paradigm for study of the self-education of iNKT cells.

Prenatal Allogeneic Tolerance in Mice Remains Stable Despite Potent Viral Immune Activation.

Transplanting stem cells before birth offers an unparalleled opportunity to initiate corrective treatment for numerous childhood diseases with minimal or no host conditioning. Although long-term engraftment has been demonstrated following in utero hematopoietic cellular transplantation during immune quiescence, it is unclear if prenatal tolerance becomes unstable with immune activation such as during a viral syndrome. Using a murine model of in utero hematopoietic cellular transplantation, the impact of an infection with lymphocytic choriomeningitis virus on prenatal allospecific tolerance was examined. The findings in this report illustrate that established mechanisms of donor-specific tolerance are strained during potent immune activation. Specifically, a transient reversal in the anergy of alloreactive lymphocytes is seen in parallel with the global immune response toward the virus. However, these changes return to baseline following resolution of the infection. Importantly, prenatal engraftment remains stable during and after immune activation. Collectively, these findings illustrate the robust nature of allospecific tolerance in prenatal mixed chimerism compared with models of postnatal chimerism and provides additional support for the prenatal approach to the treatment of congenital benign cellular disease.

Prenatal Allospecific NK Cell Tolerance Hinges on Instructive Allorecognition through the Activating Receptor during Development.

Little is known about how the prenatal interaction between NK cells and alloantigens shapes the developing NK cell repertoire toward tolerance or immunity. Specifically, the effect on NK cell education arising from developmental corecognition of alloantigens by activating and inhibitory receptors with shared specificity is uncharacterized. Using a murine prenatal transplantation model, we examined the manner in which this seemingly conflicting input affects NK cell licensing and repertoire formation in mixed hematopoietic chimeras. We found that prenatal NK cell tolerance arose from the elimination of phenotypically hostile NK cells that express an allospecific activating receptor without coexpressing any allospecific inhibitory receptors. Importantly, the checkpoint for the system appeared to occur centrally within the bone marrow during the final stage of NK cell maturation and hinged on the instructive recognition of allogeneic ligand by the activating receptor rather than through the inhibitory receptor as classically proposed. Residual nondeleted hostile NK cells expressing only the activating receptor exhibited an immature, anergic phenotype, but retained the capacity to upregulate inhibitory receptor expression in peripheral sites. However, the potential for this adaptive change to occur was lost in developmentally mature chimeras. Collectively, these findings illuminate the intrinsic process in which developmental allorecognition through the activating receptor regulates the emergence of durable NK cell tolerance and establishes a new paradigm to fundamentally guide future investigations of prenatal NK cell-allospecific education.

NK cell tolerance as the final endorsement of prenatal tolerance after in utero hematopoietic cellular transplantation.

The primary benefits of in utero hematopoietic cellular transplantation (IUHCT) arise from transplanting curative cells prior to the immunologic maturation of the fetus. However, this approach has been routinely successful only in the treatment of congenital immunodeficiency diseases that include an inherent NK cell deficiency despite the existence of normal maternal immunity in either setting. These observations raise the possibility that fetal NK cells function as an early barrier to allogeneic IUHCT. Herein, we summarize the findings of previous studies of prenatal NK cell allospecific tolerance in mice and in humans. Cumulatively, this new information reveals the complexity of the fetal immune response in the setting of rejection or tolerance and illustrates the role for fetal NK cells in the final endorsement of allospecific prenatal tolerance.

Trogocytosis as a mechanistic link between chimerism and prenatal tolerance.

In utero hematopoietic cellular transplantation (IUHCT) holds great promise for the treatment of congenital diseases of cellular dysfunction such as sickle cell disease, immunodeficiency disorders and inherited metabolic disorders. However, repeated failures in clinical cases of IUHCT that do not involve an immunodeficiency disease force a closer examination of the fetal immune system. While the mechanisms regulating T cell tolerance have been previously studied, the educational mechanisms leading to NK cell tolerance in prenatal chimeras remain unknown. As a low level of donor cells (1.8%) is required to induce and maintain this tolerance, it is likely that these mechanisms employ indirect host-donor interaction. This report examines donor-to-host MHC transfer (trogocytosis) as an intrinsic mechanism regulating the development and maintenance of NK cell tolerance in prenatal chimeras. The findings demonstrate that phenotypically tolerant host NK cells express low levels of transferred donor MHC antigens during development and later as mature cytotoxic lymphocytes. Further study is needed to understand how the cis-recognition of transferred donor MHC ligand influences the selection and maintenance of tolerant NK cells in prenatal chimeras.

Regulation of the earliest immune response to in utero hematopoietic cellular transplantation.

In Utero Hematopoietic Cellular Transplantation (IUHCT) is a promising intervention to treat a wide range of congenital disease. Through the presentation of donor cells to the immature immune system, mixed hematopoietic chimerism and donor-specific tolerance can be achieved. However, the failure of engraftment in prenatal recipients in which no immunodeficiency exists suggests the existence of a fetal immune barrier to transplantation. Although the possible barriers include effectors of the adaptive and innate immune system, our recent findings and ongoing investigations indicate that the barrier most likely resides in the developing NK cells. A chimerism level above a certain threshold during NK cell development is necessary to overcome rejection. Clinically, this transplantation barrier might also exist in early human fetal NK cells. Understanding the fetal immune barrier to allotransplantation is essential in advancing clinical application of IUHCT. Herein, we provide a short summary and new evidence for the earliest immune response to prenatal transplantation.