Cassandra M. Kelleher

Vascular extracellular matrix and aortic development.

Publisher Summary This chapter provides an observation on the vascular Extracellular Matrix (ECM) and aortic development. In addition to providing the structural and mechanical properties required for vessel function, the ECM provides instructional signals that induce, define, and stabilize smooth muscle phenotypes. There are many examples of ECM molecules playing critical roles in the regulation of gene expression by interacting with specific matrix receptors on cells, and by binding and storing growth factors that influence cellular function. This reciprocal instructive interaction between the cell and its ECM is important in directing the developmental transitions that occur in embryogenesis, postnatal development, and in response to injury. How vascular cells interpret these regulatory signals is a major area of research today. This chapter discusses the ECM molecules made by vessel wall cells during vascular development, with the primary focus on the developing mouse aorta. The concept that the ECM can influence cell proliferation, migration, and phenotypic stabilization must be considered when assessing the role of the ECM in a developing tissue.

Neonatal abdominal wall defects.

Gastroschisis and omphalocele are the two most common congenital abdominal wall defects. Both are frequently detected prenatally due to routine maternal serum screening and fetal ultrasound. Prenatal diagnosis may influence timing, mode and location of delivery. Prognosis for gastroschisis is primarily determined by the degree of bowel injury, whereas prognosis for omphalocele is related to the number and severity of associated anomalies. The surgical management of both conditions consists of closure of the abdominal wall defect, while minimizing the risk of injury to the abdominal viscera either through direct trauma or due to increased intra-abdominal pressure. Options include primary closure or a variety of staged approaches. Long-term outcome is favorable in most cases; however, significant associated anomalies (in the case of omphalocele) or intestinal dysfunction (in the case of gastroschisis) may result in morbidity and mortality.

Extracellular matrix gene expression in the developing mouse aorta

Publisher Summary This chapter discusses the vascular smooth muscle cell (SMC) phenotype and extracellular matrix (ECM) molecules made by vessel wall cells during vascular development, with the primary focus on the developing mouse aorta, and focuses on ECM gene expression during mouse aortic development. The structural matrix proteins, which are important for vascular strength and compliance, are produced during a relatively narrow developmental window in the mouse that begins around the last trimester of development and continues for only a few weeks after birth. Prior to this synthetic ‘‘matrix phase,’’ the cells in the vessel wall are highly proliferative and express matrix proteins that support cell motility, establish polarity, and bind and sequester growth factors. As the cells shift out of the matrix phase, the spectrum of contractile proteins changes as the SMC prepares for its unique contractile function and general cell maintenance genes are expressed. It is shown in the chapter that the vascular SMC can exhibit a wide range of phenotypes at different stages of development. Developing a molecular snapshot of normal development provides new avenues of investigation into vascular cell phenotypic modulation in health and disease.

Clinical outcomes in children with adrenal neuroblastoma undergoing open versus laparoscopic adrenalectomy.

BACKGROUND Laparoscopic resection of adrenal neuroblastoma has become a common alternative to open surgery. Prior reports have largely focused on short-term operative complications. This study compares long-term oncologic outcomes in children undergoing laparoscopic or open adrenalectomy for neuroblastoma. METHODS Seventy-nine patients at a single center met inclusion criteria for having adrenal neuroblastoma and undergoing operative resection. Patients were assigned to high or low/intermediate (L/I) risk groups based upon Childrens Oncology Group (COG) trial enrollment. Criteria for laparoscopic resection were absence of vascular encasement and size ≤ 5 cm in greatest dimension. Comparison between open versus laparoscopic groups was performed by Wilcoxon ranked-sum and Fishers exact test. Multivariate Cox proportional hazard models analyzed the primary outcomes of mortality and recurrence. RESULTS In the L/I risk category (N=30) there was one non-neuroblastoma related death in the open cohort. Six of 7 patients in the High risk Group who underwent laparoscopic resection had favorable outcomes. Only higher tumor stage (Hazard Ratio 8.455, P=0.01) and earlier tumor recurrence were associated with increased mortality (Hazards Ratio 0.932, P=0.0002). Among patients who met selection criteria for laparoscopic surgery there was no difference in mortality or recurrence rates between High risk and L/I risk. CONCLUSIONS Laparoscopic resection of adrenal neuroblastoma is feasible and can be performed with equivalent recurrence and mortality rates in L/I risk patients and selected High risk patients. These data suggest that laparoscopic resection of adrenal neuroblastoma should be considered in patients who meet selection criteria, irrespective of risk group categorization.

Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway

Significance This study provides the first physiological evidence, to our knowledge, that Tle1 (transducin-like enhancer of split 1) is a major negative regulator of inflammation. We show that the loss of Tle1 in mice leads to increased activity of the proinflammatory NF-κB pathway as well as decreased activity of Hes1 (hairy and enhancer of split-1), a negative regulator of inflammation. In addition, Tle1 loss resulted in decreased growth and survival with increased myelopoiesis and lung hypoplasia. Loss of Tle1 also sensitized mice to inflammatory stimuli and facilitated cancer progression. Our study opens the way to further investigations for a role of Tle1 in human inflammatory disease and cancer progression. Tle1 (transducin-like enhancer of split 1) is a corepressor that interacts with a variety of DNA-binding transcription factors and has been implicated in many cellular functions; however, physiological studies are limited. Tle1-deficient (Tle1Δ/Δ) mice, although grossly normal at birth, exhibit skin defects, lung hypoplasia, severe runting, poor body condition, and early mortality. Tle1Δ/Δ mice display a chronic inflammatory phenotype with increased expression of inflammatory cytokines and chemokines in the skin, lung, and intestine and increased circulatory IL-6 and G-CSF, along with a hematopoietic shift toward granulocyte macrophage progenitor and myeloid cells. Tle1Δ/Δ macrophages produce increased inflammatory cytokines in response to Toll-like receptor (TLR) agonists and lipopolysaccharides (LPS), and Tle1Δ/Δ mice display an enhanced inflammatory response to ear skin 12-O-tetradecanoylphorbol-13-acetate treatment. Loss of Tle1 not only results in increased phosphorylation and activation of proinflammatory NF-κB but also results in decreased Hes1 (hairy and enhancer of split-1), a negative regulator of inflammation in macrophages. Furthermore, Tle1Δ/Δ mice exhibit accelerated growth of B6-F10 melanoma xenografts. Our work provides the first in vivo evidence, to our knowledge, that TLE1 is a major counterregulator of inflammation with potential roles in a variety of inflammatory diseases and in cancer progression.

Adnexal masses in children and adolescents.

Adnexal masses in children encompass a variety of lesions of the ovaries and fallopian tubes, including ovarian cysts and tumors (benign or malignant), fallopian tube cysts and abscesses, paratubal cysts, and endometriomas. When developing a differential diagnosis for adnexal masses in childhood, the clinician must have a broad understanding of adnexal pathology and consider the patients age, presenting complaints, physical examination findings, and imaging results to generate a list of possible diagnoses and the appropriate treatment plan. We review the clinical presentation of these lesions and discuss the current recommendations for their management.

A Novel In Vitro Model to Study Alveologenesis

Many pediatric pulmonary diseases are associated with significant morbidity and mortality due to impairment of alveolar development. The lack of an appropriate in vitro model system limits the identification of therapies aimed at improving alveolarization. Herein, we characterize an ex vivo lung culture model that facilitates investigation of signaling pathways that influence alveolar septation. Postnatal Day 4 (P4) mouse pup lungs were inflated with 0.4% agarose, sliced, and cultured within a collagen matrix in medium that was optimized to support cell proliferation and promote septation. Lung slices were grown with and without 1D11, an active transforming growth factor-β-neutralizing antibody. After 4 days, the lung sections (designated P4 + 4) and noncultured lung sections were examined using quantitative morphometry to assess alveolar septation and immunohistochemistry to evaluate cell proliferation and differentiation. We observed that the P4 + 4 lung sections exhibited ex vivo alveolarization, as evidenced by an increase in septal density, thinning of septal walls, and a decrease in mean linear intercept comparable to P8, age-matched, uncultured lungs. Moreover, immunostaining showed ongoing cell proliferation and differentiation in cultured lungs that were similar to P8 controls. Cultured lungs exposed to 1D11 had a distinct phenotype of decreased septal density when compared with untreated P4 + 4 lungs, indicating the utility of investigating signaling in these lung slices. These results indicate that this novel lung culture system is optimized to permit the investigation of pathways involved in septation, and potentially the identification of therapeutic targets that enhance alveolarization.

Age Legislation and Off-Road Vehicle Injuries in Children

This study reveals the effects of comprehensive state legislation, including stringent age restrictions, on preventing ORV injuries in children. BACKGROUND AND OBJECTIVES: In 2010, the Massachusetts Legislature passed a comprehensive law that restricted off-road vehicle (ORV) use by children <14 years old and regulated ORV use by children up to the age of 18 years. We aimed to examine the impact of the 2010 Massachusetts law on the rates of ORV-related injuries. METHODS: A retrospective analysis was performed of Massachusetts emergency department (ED) and inpatient discharges between 2002 and 2013 as found in the Center for Health Information and Analysis database by using external causes of injury codes specific to ORV-related injuries. Yearly population-based rates were compared before and after the implementation of the law (2002–2010 vs 2011–2013) by using Poisson regression analysis and segmented regression. RESULTS: There were 3638 ED discharges and 481 inpatient discharges for ORV-related injuries in children across the 12-year study period. After the implementation of the law, the rate of ED discharges declined by 33% in 0- to 9-year-olds, 50% in 10- to 13-year-olds, and 39% in 14 to 17-year-olds (P < .0001). There was no significant decline in ED discharges for 25- to 34-year-olds. Inpatient hospital discharges were also reduced by 41% in 0- to 17-year-olds after implementation (P < .001). CONCLUSIONS: As compared with adults (ages 25–34 years), the population-based ORV-related injury rate of residents <18 years old significantly declined after the passage of legislation that imposed age restrictions and other safeguards for youth riders.

A population-based analysis of a rare oncologic entity: Malignant pancreatic tumors in children

PURPOSE To examine the clinicopathological characteristics and prognosis of pediatric patients with malignant pancreatic tumors in a population-based cohort. METHODS The Surveillance, Epidemiology, and End Results (SEER) database was utilized to identify all pediatric patients with malignant pancreatic tumors, diagnosed between 1973 and 2013. Kaplan-Meier analysis was performed to determine median and five-year overall survival (OS) rates. Univariate survival analysis was executed using the log-rank test. Cox proportional hazards model was used to identify variables independently associated with mortality. RESULTS A total of 114 patients with pancreatic malignancies were identified. Median patient age was 16years and the majority of patients were white (64%) females (61.4%). The most prevalent histologic subtype was neuroendocrine tumors (35.1%), whereas pancreatoblastoma was more common during the first decade of life (P<0.001). Distant metastases were noted in 41.7% of the patients, while 33.3% and 25% had localized and regional disease respectively. Five-year OS rates were 77%, 66.4% and 64.8% for patients with pancreatoblastoma, neuroendocrine and epithelial tumors respectively. No death was observed in the solid pseudopapillary tumor group. Only history of having cancer-directed surgery (CDS) was significantly associated with lower overall mortality (HR: 5.1, 95% CI: 2.1, 12.4). CONCLUSION Pancreatic malignancies are rare in children. Their prognosis is variable and only CDS was independently associated with superior survival. EVIDENCE RATING/CLASSIFICATION Prognosis study, Level II.

Is all-cause readmission an appropriate performance measure for pediatric surgeons? A case study in pyloromyotomy

INTRODUCTION All cause readmissions are used as a surrogate metric for quality of care for both hospitals and physicians, and are considered in pay for performance initiatives. However, the integrity of using all cause readmissions as a benchmark for surgical outcomes has received little attention. Pyloromyotomy for hypertrophic pyloric stenosis is considered a safe pediatric surgical procedure with few complications or readmissions. The incidence of in hospital complications has been reported, however the rate of readmissions and specifically the proportion of readmissions related to surgical complications have not been previously reported. METHODS Data were abstracted from the longitudinally linked Office of Statewide Health Planning and Development data from the State of California from 1995 to 2009, allowing patient tracking across all hospitals and years within California. Inclusion criteria were primary procedure code of pyloromyotomy, a diagnosis code of hypertrophic pyloric stenosis, and no prior record of any in-hospital admission. RESULTS A total of 1900 patients were identified: 16.8% girls, 31.7% whites, 5.1% blacks, and 58.2% Hispanics. The median length of stay was 2days (IQR 2-3days). The in-hospital complication rate was 5.16% and overall complication rate was 6.84%; there were no deaths. The rate of 30-day all-cause readmission was 4.01%, with a median of 0% across hospitals (IQR 0%-1.1%); and 13.2% of readmissions occurred at a different hospital. Surgically-related readmission rate was 2.16%. Surgically-related readmission comprised 36% readmissions at 30days, but only 13% readmissions overall. The top three primary diagnoses on readmission were respiratory infections (43%), nonrespiratory infections (14%) and other nonsurgical GI indications (14%). All-cause readmissions at 60days, 90days, 180days, and 1year were 5.8%, 7.3%, 10.4%, and 13.7%, respectively. CONCLUSION Thirty-day readmission for a surgical complication occurs in 1 of 50 patients undergoing a pyloromyotomy for hypertrophic pyloric stenosis but for all causes is twice as likely, 1 in 25 patients. All-cause readmission is an inadequate measure for the quality of surgical care and the performance of pediatric surgeons. This is a Prognostic Study with Level II Evidence.