Bioscaffold-mediated mucosal remodeling following short-segment colonic mucosal resection.

Precancerous or cancerous lesions of the gastrointestinal tract often require surgical resection via endomucosal resection. Although excision of the colonic mucosa is an effective cancer treatment, removal of large lesions is associated with high morbidity and complications including bleeding, perforation, fistula formation, and/or stricture, contributing to high clinical and economic costs and negatively impacting patient quality of life. The present study investigates the use of a biologic scaffold derived from extracellular matrix (ECM) to promote restoration of the colonic mucosa following short segment mucosal resection. Six healthy dogs were assigned to ECM-treated (tubular ECM scaffold) and mucosectomy only control groups following transanal full circumferential mucosal resection (4 cm in length). The temporal remodeling response was monitored using colonoscopy and biopsy collection. Animals were sacrificed at 6 and 10 wk, and explants were stained with hematoxylin and eosin (H&E), Alcian blue, and proliferating cell nuclear antigen (PCNA) to determine the temporal remodeling response. Both control animals developed stricture and bowel obstruction with no signs of neomucosal coverage after resection. ECM-treated animals showed an early mononuclear cell infiltrate (2 weeks post-surgery) which progressed to columnar epithelium and complex crypt structures nearly indistinguishable from normal colonic architecture by 6 weeks after surgery. ECM scaffold treatment restored colonic mucosa with appropriately located PCNA+ cells and goblet cells. The study shows that ECM scaffolds may represent a viable clinical option to prevent complications associated with endomucosal resection of cancerous lesions in the colon.

Toll-like receptor 4-mediated endoplasmic reticulum stress in intestinal crypts induces necrotizing enterocolitis.

The cellular cues that regulate the apoptosis of intestinal stem cells (ISCs) remain incompletely understood, yet may play a role in diseases characterized by ISC loss including necrotizing enterocolitis (NEC). Toll-like receptor-4 (TLR4) was recently found to be expressed on ISCs, where its activation leads to ISC apoptosis through mechanisms that remain incompletely explained. We now hypothesize that TLR4 induces endoplasmic reticulum (ER) stress within ISCs, leading to their apoptosis in NEC pathogenesis, and that high ER stress within the premature intestine predisposes to NEC development. Using transgenic mice and cultured enteroids, we now demonstrate that TLR4 induces ER stress within Lgr5 (leucine-rich repeat-containing G-protein-coupled receptor 5)-positive ISCs, resulting in crypt apoptosis. TLR4 signaling within crypts was required, because crypt ER stress and apoptosis occurred in TLR4(ΔIEC-OVER) mice expressing TLR4 only within intestinal crypts and epithelium, but not TLR4(ΔIEC) mice lacking intestinal TLR4. TLR4-mediated ER stress and apoptosis of ISCs required PERK (protein kinase-related PKR-like ER kinase), CHOP (C/EBP homologous protein), and MyD88 (myeloid differentiation primary response gene 88), but not ATF6 (activating transcription factor 6) or XBP1 (X-box-binding protein 1). Human and mouse NEC showed high crypt ER stress and apoptosis, whereas genetic inhibition of PERK or CHOP attenuated ER stress, crypt apoptosis, and NEC severity. Strikingly, using intragastric delivery into fetal mouse intestine, prevention of ER stress reduced TLR4-mediated ISC apoptosis and mucosal disruption. These findings identify a novel link between TLR4-induced ER stress and ISC apoptosis in NEC pathogenesis and suggest that increased ER stress within the premature bowel predisposes to NEC development.

Animal models of gastrointestinal and liver diseases. Animal models of necrotizing enterocolitis: pathophysiology, translational relevance, and challenges.

Necrotizing enterocolitis is the leading cause of morbidity and mortality from gastrointestinal disease in premature infants and is characterized by initial feeding intolerance and abdominal distention followed by the rapid progression to coagulation necrosis of the intestine and death in many cases. Although the risk factors for NEC development remain well accepted, namely premature birth and formula feeding, the underlying mechanisms remain incompletely understood. Current thinking indicates that NEC develops in response to an abnormal interaction between the mucosal immune system of the premature host and an abnormal indigenous microflora, leading to an exaggerated mucosal inflammatory response and impaired mesenteric perfusion. In seeking to understand the molecular and cellular events leading to NEC, various animal models have been developed. However, the large number and variability between the available animal models and the unique characteristics of each has raised important questions regarding the validity of particular models for NEC research. In an attempt to provide some guidance to the growing community of NEC researchers, we now seek to review the key features of the major NEC models that have been developed in mammalian and nonmammalian species and to assess the advantages, disadvantage, challenges and major scientific discoveries yielded by each. A strategy for model validation is proposed, the principal models are compared, and future directions and challenges within the field of NEC research are explored.

Synthetic small intestinal scaffolds for improved studies of intestinal differentiation.

In vitro intestinal models can provide new insights into small intestinal function, including cellular growth and proliferation mechanisms, drug absorption capabilities, and host-microbial interactions. These models are typically formed with cells cultured on 2D scaffolds or transwell inserts, but it is widely understood that epithelial cells cultured in 3D environments exhibit different phenotypes that are more reflective of native tissue. Our focus was to develop a porous, synthetic 3D tissue scaffold with villous features that could support the culture of epithelial cell types to mimic the natural microenvironment of the small intestine. We demonstrated that our scaffold could support the co-culture of Caco-2 cells with a mucus-producing cell line, HT29-MTX, as well as small intestinal crypts from mice for extended periods. By recreating the surface topography with accurately sized intestinal villi, we enable cellular differentiation along the villous axis in a similar manner to native intestines. In addition, we show that the biochemical microenvironments of the intestine can be further simulated via a combination of apical and basolateral feeding of intestinal cell types cultured on the 3D models.

The safe introduction of robotic surgery in a free-standing children's hospital.

The aim of this study is to report the experience of implementing a pediatric robotic surgery program at a free-standing pediatric teaching hospital. A database was created to prospectively collect perioperative data for all robotic surgeries performed by the pediatric surgery department. The database was queried for all operations completed from October 2015 to December 2021. Descriptive statistics were used to characterize the dataset, using median and interquartile ranges for continuous variables. From October 2015 to December 2021, a total of 249 robotic surgeries were performed in the department of pediatric surgery. Of the 249 cases, 170 (68.3%) were female and 79 (31.7%) were male. Across all patients, there was a median weight (IQR) of 62.65 kg (48.2-76.68 kg) and a median (IQR) age of 16 years (13-18 years). The median (IQR) operative time was 104 min (79.0-138 min). The median console time was 54.0 min (33.0-76.0 min) and the median docking time was 7 min (5-11 min). The majority of procedures were performed on the biliary tree (52.6%). In the 249 procedures, there were no technical failures of the robot and only two operations (0.8%) were converted to open procedures and one (0.4%) to laparoscopic. This study highlights the ability to successfully integrate a pediatric robotic surgery program into a free-standing children's hospital with a low conversion rate. Additionally, the program extended across multiple surgical procedures and offered real-time exposure to advanced surgical techniques for current and aspiring pediatric surgery trainees.

Pediatric Single-Incision Robotic Cholecystectomy: A 6-Year Update from a Single Institution.

Introduction: In children, gallbladder disease has become more common due to the rise in childhood obesity and subsequent shift in etiology. While the gold standard of surgical management remains a laparoscopic technique, there has been increasing interest in robotic-assisted techniques. The aim of this study is to report a 6-year update on the experience of treating gallbladder disease with robotic-assisted surgery at a single institution. Materials and Methods: A database was created to prospectively collect patient demographic and operative variables at the time of operation from October 2015 to May 2021. Descriptive analysis of select available variables was performed using median and interquartile ranges (IQRs) for all continuous variables. Results: In total, 102 single-incision robotic cholecystectomies and one single-port subtotal cholecystectomy were performed. From available data, 82 (79.6%) patients were female, median weight was 66.25 kg (IQR: 58.09-74.24 kg), and median age was 15 years (IQR: 15-18 years). Median procedure time was 84 minutes (IQR: 70.25-103.5 minutes) and median console time was 41 minutes (IQR: 30-59.5 minutes). The most frequent preoperative diagnosis was symptomatic cholelithiasis (79.6%). One (0.97%) operation was converted from a single-incision robotic approach to open. Conclusion: Single-incision robotic cholecystectomy is a safe and reliable technique for the treatment of gallbladder disease in the adolescent population.

Critical elements of pediatric neuroblastoma surgery.

Neuroblastoma (NB) is the most common solid extracranial malignancy of childhood with an incidence of 1 per 100,000 in the United States compromising approximately 10 % of childhood cancer. Unfortunately, patients with high-risk NG continue to have long-term survival less than 50 %. Both Children's Oncology Group and the International Society of Paediatric Oncology have demonstrated the important role of surgery in the treatment of high-risk NB. Herein, we compose the results of an extensive literature review as well as expert opinion from leaders in pediatric surgical oncology, to present the critical elements of effective surgery for high-risk neuroblastoma.

Pediatric sternal fractures from a Level 1 trauma center.

BACKGROUND/PURPOSE: Sternal fractures are rare in children. The purpose of this series is to document traumatic findings in pediatric patients with sternal fractures at a Level 1 trauma center. STUDY DESIGN: We reviewed the charts of patients with radiologically confirmed sternal fractures from a trauma database at a pediatric Level 1 trauma center between January 1, 2000 and December 31, 2015. We report mechanisms of injury, associated injuries, complications, and outcomes associated with sternal fractures. RESULTS: Over the 16-year period, 19/25,781 (0.07%) admitted patients had radiologically confirmed sternal fractures. 15/19 (78.9%) patients were male. The median age was 14 years, with interquartile range 10-16 years. 7/19, (36.8%) were sustained owing to motor vehicle accidents. Associated injuries included substernal hematoma (n = 6), pulmonary contusion (n = 4), vertebral injury (n = 2), rib fracture (n = 4), intraabdominal injury (n = 3), pneumothorax (n = 3), long bone injury (n = 3) traumatic brain injury (n = 2), hemothorax (n = 2), pneumomediastinum (n = 2) and cardiac contusion (n = 1). CONCLUSIONS: In this series, pediatric sternal fractures were caused by high velocity mechanisms and had significant comorbidity. While patients with isolated sternal fractures may be candidates for emergency department discharge, a thorough evaluation should be performed in children with sternal fractures to identify concurrent injuries. LEVEL OF EVIDENCE: Level IV.

Scholarly Research Projects Benefit Medical Students' Research Productivity and Residency Choice: Outcomes From the University of Pittsburgh School of Medicine.

PURPOSE: Many medical schools require scholarly research projects. However, outcomes data from these initiatives are scarce. The authors studied the impact of the Scholarly Research Project (SRP), a four-year longitudinal requirement for all students at the University of Pittsburgh School of Medicine (UPSOM), on research productivity and residency match. METHOD: The authors conducted a longitudinal study of non-dual-degree UPSOM graduates in 2006 (n = 121, non-SRP participants) versus 2008 (n = 118), 2010 (n = 106), and 2012 (n = 132), all SRP participants. The authors used PubMed for publication data, National Resident Matching Program for residency match results, and Blue Ridge Institute for Medical Research for National Institutes of Health funding rank for residency-affiliated academic institutions. RESULTS: Research productivity of students increased for those completing the SRP, measured as a greater proportion of students with publications (27.3% in 2006 vs. 45.8% in 2008, 55.7% in 2010, and 54.5% in 2012; P < .001) and first-authorship (9.9% in 2006 vs. 26.3% in 2008, 33.0% in 2010, and 35.6% in 2012; P < .001). Across years, there was a significantly greater proportion of students with peer-reviewed publications matched in higher-ranked residency programs (57.0% with publications in the top 10%, 52.7% in the top 10%-25%, 32.4% in the top 25%-50%, 41.2% in the bottom 50%, and 45.2% in unranked programs; P = .018). CONCLUSIONS: Longitudinal research experiences for medical students may be one effective tool in fostering student publications and interest in extending training in a research-focused medical center.

Intestinal stem cell growth and differentiation on a tubular scaffold with evaluation in small and large animals.

AIMS: To investigate the growth and differentiation of intestinal stem cells on a novel tubular scaffold in vitro and in vivo. MATERIALS & METHODS: Intestinal progenitor cells from mice or humans were cultured with myofibroblasts, macrophages and/or bacteria, and evaluated in mice via omental implantation. Mucosal regeneration was evaluated in dogs after rectal mucosectomy followed by scaffold implantation. RESULTS: Intestinal progenitor cells differentiated into crypt-villi structures on the scaffold. Differentiation and scaffold coverage was enhanced by coculture with myofibroblasts, macrophages and probiotic bacteria, while the implanted scaffolds enhanced mucosal regeneration in the dog rectum. CONCLUSION: Intestinal stem cell growth and differentiation on a novel tubular scaffold is enhanced through addition of cellular and microbial components, as validated in mice and dogs.