Congenital cystic lung malformations encompass a diverse group of lesions that arise during in utero development. A variety of pathologic classification schemes have been proposed, but recent advances suggest that gross and microscopic morphologies can often be explained by the underlying mechanism of cyst development. A subset of congenital pulmonary airway malformations, usually with large cysts, is associated with widespread epithelial oncogenic KRAS mutation. These have a long-term risk of developing mucinous adenocarcinoma. Another subset, more commonly with smaller cysts, are associated with bronchial atresia or other mechanisms of obstruction. The histology of atresia specimens overlaps with that of intra- and extra-lobar sequestrations, which additionally have an extra hilum-like structure suggesting that they arise due to an ectopic portion of lung developing without normal fluid-flow in utero. These lesions are not expected to have a long-term risk of cancer but may become infected due to abnormal clearance. Finally, a subset of lesions associated with DICER1 mutation may arise in utero or after birth and are best classified as cystic pleuropulmonary blastoma. The term congenital pulmonary airway malformation is no longer in use for these cysts, which may progress to a solid aggressive sarcoma or may regress to a bland and benign multiloculated cyst. While surgical management may be the same independent of the underlying pathology (open or thoracoscopic lobectomy), post-natal pathologic examination contributes to patient care by establishing a diagnosis that goes beyond cyst size. This may guide future treatment decisions including monitoring, molecular testing, or genetic counseling.
Appendicitis remains the most common surgical emergency in children and adolescents, yet its epidemiology and pathophysiology remain incompletely understood. Studies have demonstrated substantial geographic, racial, temporal, and socioeconomic variation in appendicitis incidence and severity. Advances in population-based investigation, imaging, and microbiome analysis have further challenged the traditional concept of appendicitis as a uniform disease process caused solely by luminal obstruction. Increasing evidence instead supports a multifactorial process influenced by environmental exposures, host susceptibility, microbial factors, and healthcare access. Epidemiologic observations additionally suggest important differences between uncomplicated and perforated appendicitis. Improved understanding of these relationships has important implications for disease classification, risk stratification, and future treatment strategies. This review summarizes the current understanding of the incidence, epidemiologic trends, and pathophysiology of pediatric appendicitis.
It is reasonable to offer nonoperative management (NOM) of acute uncomplicated appendicitis as an alternative treatment option to appendectomy in cases meeting established evidence-based criteria. As public awareness of this option has increased, patients and families are more likely to inquire about NOM. Shared decision-making (SDM) is well suited for instances where there is not one clear recommended treatment option, as it allows the patient and family's preferences and values to be prioritized. When applying SDM to the pediatric patient, both the patient and the family should be included in the decision-making process. We provide case-based examples of SDM for determining the treatment course for pediatric patients with acute uncomplicated appendicitis.
Pediatric intestinal failure resulting from short bowel syndrome remains a significant source of morbidity and mortality despite advances in parenteral nutrition and multidisciplinary intestinal rehabilitation. While native intestinal adaptation provides a foundation for recovery in many patients, those with the most severe forms of short bowel syndrome face limited therapeutic options, including lifelong parenteral nutrition dependence, surgical lengthening procedures, and intestinal transplantation-each associated with substantial complications. The field of bowel regeneration has expanded dramatically over the past two decades, drawing on advances in stem cell biology, biomaterials science, mechanotransduction, and bioengineering. This review examines the current landscape of bowel regeneration strategies through a conceptual framework that progresses from native adaptation, through cellular and biological therapies, to structural and mechanical approaches, and ultimately to tissue engineering as the integration of cellular and structural strategies. Emerging technologies including gene editing for regional reprogramming of intestinal identity, three-dimensional bioprinting, and advanced organoid-scaffold systems are discussed as they relate to the future of clinical translation. Although significant hurdles remain-particularly in vascularization, innervation, and scaling of engineered constructs-the trajectory of the field suggests that regenerative approaches may fundamentally alter the management of pediatric intestinal failure within the coming decades.
Pediatric hepatobiliary diseases can progress to liver failure and transplantation, yet donor scarcity, lifelong immunosuppression, and cumulative graft-related morbidity remain major limitations. Regenerative medicine offers complementary strategies for disease modelling, therapeutic discovery, tissue repair, and clinical decision-making. Patient-derived organoids and microphysiological systems can reproduce disease-specific epithelial phenotypes, support drug screening, and provide mechanistic or prognostic information in conditions such as biliary atresia and inherited cholestatic disorders. Cell-based therapies may provide temporary metabolic support but remain constrained by limited engraftment and dilution during liver growth. Repeatable mRNA delivery may accommodate rapid hepatic expansion, whereas a successfully installed genomic edit may remain durable even during active hepatic proliferation. Surgical strategies, including portal vein embolization and selected partial ALPPS, exploit endogenous regeneration to increase the future liver remnant when major resection is required. In pediatric acute liver failure, extracorporeal support can provide temporary metabolic and physiological stabilization while native-liver recovery and transplant candidacy are assessed. We propose a developmental and disease-specific framework integrating structural integrity, clinical urgency and trajectory, and developmental stage. This framework is intended to guide multidisciplinary assessment of when regenerative or supportive strategies remain appropriate and when transplant evaluation should be escalated, rather than to define universal treatment thresholds.
Myelomeningocele (MMC), the most severe form of spina bifida, is currently the only non-lethal condition for which prenatal surgery is performed. This paradigm was established by a randomized trial demonstrating that prenatal intervention reduced shunt rates for hydrocephalus and improved distal neurologic function compared with postnatal repair. There is continued motivation to further improve outcomes for these patients using a variety of regenerative strategies, both explored in the basic science/translational literature and in current practice. In this narrative review, we begin with an overview of the rationale and history of prenatal MMC repair, then describe regenerative strategies including biomaterial-based approaches and early phase clinical trials of stem-cell augemented repairs.
Organoids are three-dimensional structures derived from a single stem cell. They self-organize in vitro and mature to recreate microarchitecture and characteristics of their tissues of origin. Since the first culture of mouse intestinal epithelial organoids and the translation to human, this technology has shown vast potential. Applications include developmental biology, disease modelling, drug testing and regenerative medicine making it increasingly relevant to clinical practice. Organoids can now be generated from tissues such as lung, intestine, kidney and brain using adult and fetal stem cells, pluripotent stem cells and cancer samples. Whether to study fetal development, disease physiopathology, regenerative medicine or to develop new therapies in a faster, more ethical and cost-effective way than animal models, organoids represent a powerful new tool.First described in 1999, personalised medicine aims to fine-tune diagnostic, prognosis and treatment to each patient. Nowadays, personalised medicine is spreading to most areas of clinical management, becoming the gold standard for the adoption of new interventions. More recently, these concepts have been applied to fetal medicine for prevention and therapy with initial reports appearing in literature in 2020.By recapitulating patient-specific disease mechanisms, prenatal organoids represent a unique bridge between in vitro-based approaches and personalised fetal medicine. This review presents fetal diseases for which organoids were explored, focusing on the implications of their derivation from prenatal sources such as the amniotic fluid, and discusses their advantages, challenges, and perspectives for prenatal counselling, prognosis or diagnosis, regenerative therapy, in utero surgery, disease modelling and prenatal drug testing.
While pediatric appendicitis is one of the most common conditions managed by both pediatric emergency medicine physicians and pediatric surgeons, disparities in pediatric appendicitis care are well-documented. Black and Hispanic children are more likely to have a delayed diagnosis of appendicitis. Furthermore, black children, Hispanic children, and children from low Child Opportunity Index-neighborhoods are more likely to present with complicated appendicitis. Differences in care persist even after the diagnosis of appendicitis and are largely influenced by a child's sociodemographic background. Cuts to Medicaid and CHIP as a result of the One Big Beautiful Bill Act may lead to even more disparate care for at-risk patients.
Non-operative management (NOM) for children with uncomplicated appendicitis has emerged as a safe alternative to appendectomy. Despite increasing adoption, uncertainty persists regarding optimal patient selection, outcome interpretation, and real-world implementation. Variability in trial design, outcome definitions, and clinician perspectives have further contributed to ongoing debate surrounding the role of NOM in contemporary pediatric care. This review synthesizes current evidence evaluating the safety, effectiveness, and patient-centered outcomes of NOM for uncomplicated appendicitis in children, with an emphasis on practical guidance for clinicians navigating management decisions through shared decision-making with patients and their families.
Complicated appendicitis, in which the appendix has perforated, is a well-studied pediatric surgical condition. Despite this, practice management varies widely among institutions. Both suspected and confirmed perforation present unique challenges beyond those of acute uncomplicated appendicitis, namely increased healthcare utilization and a higher incidence of postoperative abscess. Debate continues regarding the role and timing of appendectomy, as well as antibiotic choice and duration to mitigate these challenges. There are developing new initiatives that target different aspects of management in the hopes of reducing overall morbidity and sequela. In this article, we discuss the history and current management of complicated appendicitis in children, along with emerging developments in the field.
Extracellular vesicles (EVs) are lipid bilayer-delimited nanoparticles released by cells to act as mediators of intercellular communication during organ development, injury, and repair. EVs carry cargo (bioactive proteins, lipids, and nucleic acids) that reflects the status of the parent cell and is transferred to recipient cells to regulate biological processes, such as inflammation, immune responses, and tissue regeneration. These properties have made EVs promising tools for investigating disease pathogenesis, improving diagnostic and prognostic accuracy, and developing cell-free regenerative therapies for conditions characterized by dysregulation of multiple biological pathways. EVs are particularly relevant in diseases that affect the pediatric population where pathogenesis often remains poorly understood, access to affected tissues is limited, and treatment options are frequently inadequate. This review summarizes current evidence on EV applications in fetal and neonatal disorders, including necrotizing enterocolitis, congenital diaphragmatic hernia, and bronchopulmonary dysplasia, and highlights emerging data in biliary atresia, spina bifida, short bowel syndrome, and Hirschsprung’s disease. In this age group, human milk and amniotic fluid represent particularly attractive biologically accessible sources of EVs, combining therapeutic potential with feasibility of clinical application. Building on robust preclinical evidence, the field is now advancing toward clinical translation, but several aspects still need to be addressed such as cargo heterogeneity, scalability of production, dosing, biodistribution, safety, and regulatory standardization. Herein, we discuss the translational challenges and future directions that will shape the clinical application of EVs in perinatal conditions.
Children with congenital foregut malformations including tracheal pathology or long-gap esophageal atresia have limited treatment options. Severe malformations have suboptimal replacement options for both congenital and acquired anomalies despite maximal surgical intervention. Tissue engineering offers a potential solution to address this unmet need.For esophageal reconstruction, the combination of decellularized extracellular matrix scaffolds, myogenic progenitor cells, and bioreactor pre-conditioning has shown the most promising preclinical results. For tracheal replacement, there have been initial reports in pediatric patients, but no strategy has yet demonstrated consistent preclinical success, and the optimal approach remains to be defined. The two fields are at markedly different stages of translational readiness. Tracheal tissue engineering has not yet achieved consistent safety or durability in orthotopic large-animal models, and clinical use has been confined to a small number of compassionate-use cases with mixed outcomes partly related to inconsistent use of scaffold materials and cell replacement strategies. Esophageal reconstruction is closer to clinical translation, with a clinical trial of segmental replacement in adults underway and full-thickness circumferential replacement with evidence of secondary peristalsis demonstrated in a growing large-animal model.Pediatric patients impose unique constraints for tissue engineering but also offer advantages, including enhanced tissue remodeling capacity. Bridging the gap between current preclinical progress and safe clinical application will demand robust animal model validation, transparent documentation of setbacks, and sustained interdisciplinary engagement.This review summarizes current strategies for tracheal and esophageal reconstruction using tissue-engineered approaches, evaluating preclinical and clinical evidence across scaffold design, cell sourcing, and vascularization.
Transamniotic stem cell therapy (TRASCET) constitutes the least invasive approach to prenatal stem cell delivery described to date. This strategy is largely based on the recently discovered active transport of donor cells from the amniotic fluid to the placenta directly through the amnio-placental interface. From a simple amniocentesis, via the placenta, donor cells of different phenotypes can reach the fetal circulation and virtually any fetal anatomical site, including, and particularly, the fetal bone marrow. As a result, TRASCET has shown broad therapeutic potential in an assortment of animal models. First reported experimentally only a little over a decade ago, it has yet to be attempted clinically, though clinical translation may be imminent. Much of TRASCET's appeal lies in the fact that, in large part, it constitutes a form of replenishment therapy based on the magnification of naturally occurring processes in the distinctive environment of the maternal-fetal unit. Despite significant experimental advances, much promise and perhaps excessive publicity, most cell-based therapies have yet to deliver meaningful large-scale impact to patient care. The few exceptions have been therapies based on the amplification of the normal biological role played by donor cells in their natural environment. TRASCET falls in that category. Further, while fetal stem cells possess unique characteristics when compared with postnatal stem cells, so does the fetus when compared with any other age group, converging into a scenario that enables therapeutic paradigms exclusive to prenatal life. This review summarizes the biological basis, diversity of applications and operability of the TRASCET principle.
Advances in preconception and prenatal genetic testing, in combination with the rapid evolution and regulatory acceptance of targeted gene therapy technologies, has unveiled promising opportunities for the antenatal treatment of genetic disease by way of in utero gene editing and precision medicine. Recent regulatory guidance, put forth by the Federal Drug Administration (FDA), on gene editing has the exciting potential to accelerate the development and implementation of therapeutics for rare and ultrarare diseases. In this review, we highlight recent advances that have occurred in the fields of in utero gene editing and precision medicine and the opportune regulatory landscape that may facilitate the clinical translation of therapeutics in the future. We additionally review the indispensable role of prenatal genetic diagnosis, including chorionic villus sampling, amniocentesis, and noninvasive prenatal testing, as the diagnostic gateway through which candidates for in utero gene and precision therapies will be identified.
The EXtra-uterine Environment for Neonatal Development (EXTEND) was developed to support extremely premature infants (EPIs) with the goal to mimic in-utero conditions as closely as possible and therefore reduce morbidity and mortality associated with organ immaturity and iatrogenic injury caused by current neonatal management. In an animal model using fetal lambs at a gestational age equivalent to EPIs of 22-24 weeks of gestation, EXTEND was able to support fetuses for up to four weeks while enabling normal organ growth, particularly normal lung development. Recent advances in EXTEND have allowed this technology to come closer to clinical translation than ever before. In a broader future context, EXTEND can be viewed as a platform to facilitate treatment of a variety of disorders such as intrauterine growth restriction, congenital heart disease, congenital diaphragmatic hernia, and genetic or cellular disorders where treatment would otherwise carry risk to the mother or require extensive and direct access to the fetus.
Appendicitis serves as a model for pathway-driven quality improvement (QI) in pediatric surgical care. The high case volume, predictable clinical trajectory, and measurable outcomes associated with acute appendicitis care facilitate identification of unwarranted practice variation and allow standardization to be feasible at scale. Starting in the mid-2010s, several QI initiatives transformed appendicitis management in children. This review highlights four QI efforts in pediatric appendicitis management including the shift of diagnostic imaging from routine computed tomography to ultrasound-first strategies, improved opioid stewardship, de-implementation of low-value practices such as routine total parenteral nutrition utilization, and generation of severity-guided clinical practice guidelines that decreased postoperative antibiotic durations. Across these domains, improvement followed a consistent progression through phases of documented variation, evidence consolidation, structured local implementation, guideline alignment, and eventually sustained monitoring of guideline-based practices. Continued progress will require ongoing development of pediatric-specific evidence, dissemination of evidence-based practices into broader practice settings, and focused efforts to ensure equitable implementation across populations. QI efforts for appendicitis serve as a transferable blueprint for value-based and safety-focused pediatric care, demonstrating that unwarranted variation can be reduced when evidence-based practices are embedded into structured clinical guidelines, process metrics and outcomes are measured transparently, and principles are reinforced through coordinated dissemination.
INTRODUCTION:Children with congenital anomalies often require surgical intervention. Long-term follow-up guidelines are heterogeneous. Our aims were to 1) determine the time to latest complication after index surgery to tailor our follow-up program, and 2) query family attitudes toward long-term follow-up by our clinic. These efforts are intended to plan future quality improvement work at our institution. METHODS:This is a single center retrospective review of patients treated between January 2015- January 2026 with congenital diaphragmatic hernia, congenital pulmonary airway malformation, bronchopulmonary sequestration, choledochal cyst, gastroschisis, omphalocele, intestinal atresia, sacrococcygeal teratoma, and esophageal atresia with tracheoesophageal fistulae. We abstracted age at index operation, complications, their timing, and subsequent operations. An internally developed survey was used to assess potential advantages and disadvantages to long-term follow up. RESULTS:292 patients met inclusion criteria (55 CDH, 26 CPAM, 14 choledochal cyst,16 BPS, 49 gastroschisis, 15 omphalocele, 57 atresia, 10 SCT, 50 TEF). Median follow-up was 3.5 yrs (range first follow-up after birth hospitalization to 19.9 yrs). Common complications requiring surgery more than one year post-operatively were bowel obstruction (n = 7) and ventral/incisional hernias (n = 4). We observed late recurrence in CDH and SCT. Survey results (n = 52) indicate families believe the potential benefits of long-term surgical follow-up (surveillance, longitudinal care) outweigh the potential disadvantages of follow up (schedule, cost, stress). CONCLUSION:Surveillance of anomalies is valuable. For some patients with specific anomalies, parental education and pediatrician oversight may be sufficient. Importantly, families perceive an annual follow-up to be beneficial, underscoring the importance of incorporating family perspectives when building and adopting protocols.
The U.S. Department of Defense Joint Trauma System (JTS) has transformed battlefield trauma care through data-driven performance improvement, standardized guidelines, and continuous feedback. Lessons learned from pediatric wartime casualties in Iraq and Afghanistan, spanning more than two decades, have extended beyond combat, influencing how civilian pediatric trauma and disaster systems prepare for and manage mass-casualty incidents (MCIs). This manuscript examines the historical development of military trauma systems, the evaluation of Critical Care Air Transport Teams (CCATT), and the translation of Combat Casualty Care (CCC) principles, such as tourniquet use, tranexamic acid (TXA), and balanced transfusion, into civilian pediatric practice. These innovations demonstrate how military-derived frameworks continue to shape pediatric preparedness, trauma resuscitation, and disaster response across both prehospital and hospital domains.
