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Children with severe constipation and a neurodiverse disorder (Autism and/or developmental delay) represent a challenging bowel management group. Treatment outcomes with laxative or enema therapy remain limited and are often complicated by patient/caregiver compliance. We hypothesized that children with neurodiverse disorders and severe constipation would benefit from a bowel management program (BMP) that includes early use of antegrade enemas.Children requiring BMP in the Pediatric Colorectal and Pelvic Learning Consortium (PCPLC) registry with diagnosis of constipation and/or constipation with pseudo-incontinence were reviewed. Those with Hirschsprung disease and/or Anorectal Malformation were excluded. BMP needs in patients with a neurodiverse diagnosis were compared to those without to evaluate differences in BMP's.372 patients requiring a BMP were identified. 95 patients (58 autism spectrum, 54 developmental delay) were neurodiverse, and 277 patients were not. Neurodiverse patients had a higher prevalence of enema therapy 62.1% (59/95) vs. 54.9% (152/273) and use of antegrade enema therapy 33.7% (32/95) vs. 21.2% (58/273), p = 0.126. Neurodiverse patients were older 37.9% (36/95)12 years vs. 23.1% (63/273), p = 0.001 and 47.6% (10/21) were changed from laxative to enema therapy over time. 80% (8/10) of those changed from laxatives to enemas used antegrade therapy. 67.3% (35/52) of neurodiverse patients followed over time were on enema therapy at the most recent visit with 80% (28/35) requiring antegrade therapy.A large portion of patients with a neurodiverse disorder who fail laxative therapy use antegrade enemas to achieve effective bowel management. Early consideration of an antegrade conduit may simplify treatment in this group of children.III.

Item does not contain fulltext BACKGROUND: VACTERL association is defined by the presence of 3 or more anomalies in any of the following systems: vertebral, anorectal, cardiac, trachea-esophageal, renal, or limb. This study hypothesized that the presence of VACTERL association would correlate with an increased risk of gynecologic anomalies in patients with anorectal malformation (ARM). METHODS: This study is a cross-sectional, retrospective analysis from the prospectively collected, multicenter registry of the Pediatric Colorectal and Pelvic Learning Consortium (PCPLC). The 834 female patients with ARM who were enrolled in the registry by January 1, 2020 were included in this study. The relationship of VACTERL association with presence of a gynecologic anomaly was evaluated with Fisher's exact test. The relationship of each VACTERL system with presence of a gynecologic anomaly was assessed in patients with cloaca, rectovestibular fistulas and rectoperineal fistulas. P-values reported were based on a 2-sided alternative and considered significant when less than 0.05. RESULTS: 834 patients with ARM underwent VACTERL screening and gynecologic evaluation with the three most common subtypes being cloaca (n = 215, 25.8%), rectovestibular fistula (n = 191, 22.9%) and rectoperineal fistula (n = 194, 23.3%). A total of 223 (26.7%) patients with ARM had gynecologic anomalies. VACTERL association was seen in 380 (45.6%) of patients with ARM. Gynecologic anomalies were present in 149 (39.1%) vs. 74 (16.3%) of subjects with vs. without VACTERL association (p < 0.001). VACTERL association did not significantly increase the risk of gynecologic anomaly in patients with cloaca and VACTERL (n = 88, 61.5%) vs. cloaca without VACTERL (n = 39, 54.2% p = 0.308). VACTERL association increased the risk of gynecologic anomalies in patients with rectoperineal fistulas (n = 7, 14.9% vs n = 9, 6.1% p = 0.014) and rectovestibular fistulas (n = 19, 31.1% vs. n = 13, 10.0% p

OBJECTIVE Infants requiring intestinal resection because of necrotizing enterocolitis (NEC) or small bowel atresia (SBA) may benefit from mucous fistula refeeding (MFR) of enterostomy output to improve nutrition and bowel adaptation before reanastomosis. Previous series demonstrated improved outcomes with MFR but did not account for varied patient characteristics as potential sources of bias. We performed a cohort analysis using multivariable adjusted models to compare outcomes of patients with and without MFR. METHODS Retrospective chart review was performed for patients with NEC or SBA and small bowel resection with enterostomy and MF. Demographic and outcome data was compared between MFR and non-MFR groups using adjusted multivariable analysis for potential confounding variables. RESULTS MFR was performed in 65 of 101 patients (64%), including 45 of 75 patients with NEC and 20 of 26 patients with SBA. Reasons for not receiving MFR included bowel stricture, technical limitation, or not otherwise specified. NEC patients receiving MFR had 14 fewer days to achieve full enteral feeds after intestinal reconnection, 22 fewer days of parenteral nutrition, lower peak direct bilirubin by 2.4 mg/dL, and 77% less odds of ursodiol use (all P

Background/Purpose the timing of endorectal pull-through for Hirschsprung disease (HD) is controversial. Neonatal primary endorectal pull-through theoretically prevents preoperative enterocolitis. Delayed primary endorectal pull-through offers the surgeon the benefit of more robust perineal anatomy and allows primary caregivers the time to emotionally process the diagnosis and to gain experience with rectal irrigations. We hypothesized that delayed primary endorectal pull-through would be associated with equivalent perioperative morbidity compared to the neonatal repair and would lead to improved long-term functional outcomes. Methods we analyzed all patients in the Pediatric Colorectal and Pelvic Learning Consortium (PCPLC) registry who had a primary endorectal pull-through for HD and at least three-and-one-half years of follow up in a specialty colorectal clinic. We evaluated patient demographics, operative outcomes, perioperative episodes of enterocolitis, and long-term functional outcomes for the neonatal ( Results eighty-two patients were identified of whom 49 were operated upon in the neonatal period and 33 in a delayed fashion. The median age at operation was 11 days [IQR 7 – 19 days] for the neonatal cohort and 98 days [IQR 61 – 188 days] for the delayed cohort. Thirty-four (69.4%) of the neonatal and 22 (66.7%) of the delayed cohort patients had rectosigmoid transition zones. Four of 49 patients (8.1%) in the neonatal cohort were diagnosed with enterocolitis preoperatively compared to two of 33 (6.0%) in the delayed cohort (p = 0.89). Eighteen of 49 patients (36.7%) in the neonatal cohort and 16 of 33 (48.5%) in the delayed cohort had at least one postoperative episode of enterocolitis (p = 0.38). Fifteen of 49 patients (30.6%) in the neonatal cohort were receiving bowel management for fecal incontinence at most recent follow up compared to five of 33 (15.2%) in the delayed cohort (p = 0.13). Conclusion delayed primary endorectal pull-through offers a safe alternative to operation in the neonatal period and appears to have, at least, equivalent functional outcomes. Level of evidence : Level III, retrospective comparative study

Purpose The purpose of this study was to compare the postoperative outcomes of neonatal versus delayed repair of rectoperineal and rectovestibular fistulae using a multi-center pediatric colorectal specific database. We hypothesized that the incidence of 30-day postoperative complications is not significantly different between these two surgical treatment strategies. Methods We performed a retrospective, observational study of the Pediatric Colorectal and Pelvic Learning Consortium (PCPLC) database. We included any patient from the database that underwent primary surgical repair of a rectoperineal or rectovestibular fistula. Neonatal repair was defined as occurring within 14 days of birth, and delayed repair as occurring after that period. The primary outcome was the occurrence of postoperative complications within 30 days. Results 164 patients were included in the study (123 rectoperineal, 41 rectovestibular); the majority (81%) were repaired in a delayed fashion. Patients that underwent delayed repair had lower birth weights and were more likely to be female than those that underwent neonatal repair. Wound breakdown/dehiscence was the most common complication in both groups (Delayed 5.3% v. Neonatal, 6.5%). We found no significant difference in the incidence of any postoperative complication between groups (Delayed 6.0 v. Neonatal 6.5%, p = 1.0). Conclusion We concluded there was no significant difference in the incidence of 30-day postoperative complications for neonatal versus delayed repair of rectoperineal and rectovestibular fistulae, suggesting that both strategies are safe and may have excellent short-term outcomes in appropriately selected patients.

Fecal continence is a concern for many patients with idiopathic constipation and can significantly impact quality of life. It is unknown whether racial, ethnic, and socioeconomic disparities are seen in fecal continence within the idiopathic constipation population. We aimed to evaluate fecal continence and associated demographic characteristics in children with idiopathic constipation referred for surgical evaluation.A multicenter retrospective study of children with idiopathic constipation was performed at sites participating in the Pediatric Colorectal and Pelvic Learning Consortium (PCPLC). All patients3y of age with idiopathic constipation diagnosis were included. The primary outcome was fecal continence, categorized as complete (no accidents ever), daytime (no accidents during the day), partial (occasional incontinence day/night), and none (incontinent). We evaluated for associations between fecal continence and race, sex, age, insurance status, and other patient-level factors, employing Kruskal-Wallis and trend tests.458 patients with idiopathic constipation from 12 sites were included. The median age of diagnosis was 4.1 years. Only 25% of patients referred for surgical evaluation were completely continent. Age at the visit was significantly associated with fecal continence level (p = 0.002). In addition, patients with public and mixed public and private insurance had lower levels of continence (p0.001). Patients with developmental delay were also more likely to have lower continence levels (p = 0.009) while diagnoses such as anxiety, ADD/ADHD, autism, depression, obsessive-compulsive disorder were not associated. Approximately 30% of patients had an ACE operation (antegrade continence enema) at a median age of 9.2 years at operation. Black patients were significantly less likely to undergo ACE operation (p = 0.016) when compared to white patients.We observed data that suggest differences in fecal incontinence rates based on payor status. Further investigation is needed to characterize these potential areas of disparate care.Level III.

To describe current bowel management program (BMP) strategies in anorectal malformation (ARM) patients based on patient-level predictors using data from a multi-institutional consortium.Patient bowel function and BMP were reviewed from Pediatric Colorectal and Pelvic Learning Consortium (PCPLC) data. The PCPLC is comprised of multidisciplinary specialists researching colorectal and pelvic disorders. Seven US institutions submitted de-identified clinical data on ARM patients into a centralized patient registry.The primary ARM of 624 patients was categorized into Mild (45.2%), Moderate (40.4%) or Complex (14.2%) anomaly classifications. Patient-specific BMP were examined based on age and on the presence of spinal cord/sacral anomalies. 418 (67%) enrolled patients were prescribed BMP (5 yo 56.4%; ≥5-12 yo 86.7%; ≥12 81.5%). Constipation was the primary chief complaint (80.2%). Forty percent of patients on a BMP were toilet trained and approximately one-half (48.5%) reported daytime stool accidents. Secondary surgical interventions for antegrade continence enemas (ACE) were examined; 14.5% of patients employed ACE strategies and utilization increased with age and varied based on anatomic anomalies.This is the first report on BMP strategies for patients with ARM from the Pediatric Colorectal and Pelvic Learning Consortium. Individual patient characteristics are explored for their impact on bowel management strategy utilization.IV.

Botulinum toxin (BT) is used to treat pediatric patients with Hirschsprung disease (HD) with obstructive symptoms. We aimed to characterize use of BT in HD patients across pediatric colorectal surgery referral centers.A multicenter retrospective study of BT use in children (0-18y) with HD was performed using the Pediatric Colorectal and Pelvic Learning Consortium (PCPLC) between 2017 and 2021. Sites with10 HD patients recorded were excluded. Patterns were evaluated using Fisher's exact, Wilcoxon rank-sum, Kruskal-Wallis, and Cochran-Armitage trend test.494 patients at 8 centers were included. 118 (23.9%) received at least one BT injection. Among patients who required redo pullthrough procedures, 53.1% received BT compared to 22.7% of patients who only underwent one pullthrough (p0.001). Age at pullthrough was also significantly associated (p = 0.021). A lower proportion of Hispanic patients received BT (9.6% vs. 26.3%;p = 0.006). Percentage of HD patients receiving BT varied significantly across sites (p0.001).Use of BT in patients with HD varies widely with greater use in patients who underwent redo surgery and in those who underwent pullthrough at an older age. Hispanic patients received less BT. These findings highlight the need to develop consensus guidelines and for further study on timing of injections and potential disparities in care.III.

Purpose While fecal incontinence is a primary concern for many children with anorectal malformations (ARM), urinary incontinence is also prevalent in this population. Racial, ethnic, and socioeconomic disparities in urinary continence have been observed in other conditions, but have not been previously evaluated in ARM. We aimed to evaluate urinary continence and associated demographic and socioeconomic characteristics in individuals with ARM. Methods We performed a multicenter retrospective study of ARM patients evaluated at sites participating in the Pediatric Colorectal and Pelvic Learning Consortium (PCPLC). We included all patients with ARM 3 years and older. The primary outcome was urinary continence which was categorized as complete (no accidents), daytime (accidents at night), partial (rare or occasional accidents), and none (frequent accidents or no continence). We evaluated for associations between urinary continence and race, sex, age, insurance status, and adoption status, employing Kruskal-Wallis and trend tests. Secondary outcomes included bladder management strategies such as clean intermittent catheterization and continence surgery. P-value Results A total of 525 patients with ARM were included. Overall, 48% reported complete urinary continence, and continence was associated with greater age. For school-aged children (age ≥ 5 years), 58% reported complete continence, while 30% reported none. Public insurance and adoption status were associated with decreased likelihood of incontinence. Conclusions We observed a novel finding of disparities in urinary continence for children with ARM related to insurance and adoption status. Further investigation regarding the etiologies of these inequities is needed in order to affect clinical outcomes.

Purpose The aim of this study was to determine long-term outcomes for congenital diaphragmatic hernia (CDH) patients including quality of life (QoL), symptom burden, reoperation rates, and health status. Methods A chart review and phone QoL survey were performed for patients who underwent CDH repair between 2007 and 2014 at a tertiary free-standing children’s hospital. Comprehensive outcomes were collected including subsequent operations and health status. Associations with QoL were tested using Wilcoxon Rank-Sum tests and Pearson correlation coefficients. Results Of 102 CDH patients identified, 46 (45.1%) patient guardians agreed to participate with mean patient age of 5.8 (SD, 2.2) years at time of follow-up. Median PedsQLTM and PedsQLTM Gastrointestinal scores were 91.8 (IQR, 84.8–95.8) and 95.8 (IQR, 93.0–98.2), out of 100. Thoracoscopic repair was associated with higher PedsQLTM scores while defects with an intrathoracic stomach were associated with increased gas and bloating. No difference in QoL was found when comparing defect side, patch vs primary repair, prenatal diagnosis, extracorporeal membrane oxygenation, or recurrence. Older age weakly correlated with worse school functioning and heartburn. Conclusion Children with CDH have reassuring QoL scores. Given the correlation between older age and poor school function, longer follow-up of patients with CDH may be warranted. Level of Evidence III (Retrospective comparative study).

Hirschsprung disease (HD) is a complex surgical and medical problem that appears to have varied health and social outcomes with the age and neurodevelopmental state of patients. In general, long-term outcomes are thought to be good for the majority of patients despite recognized problems with constipation and/or fecal incontinence. However, there are no universally accepted pathways regarding post-operative bowel management programs nor clearly defined follow-up pathways making the current outcome measures difficult to interpret. Further, other factors that may influence outcome including age at the time of procedure and procedure type continue to lack consensus. Improved support of children in resource limited environments and during periods of transition into the adult medical care environment are needed to improve outcome. Recent proliferation of multidisciplinary care teams and consortia may help to better understand outcomes and address current knowledge gaps. Continuing these collaborations will be imperative to continuing improvements in care which may ultimately impact outcome.

Introduction The current understanding of Hirschsprung-associated enterocolitis (HAEC) is based mainly on single-center, retrospective studies. The aims of this study are to determine risk factors for postoperative HAEC using the Pediatric Colorectal and Pelvic Learning Consortium (PCPLC) database. Materials and Methods We performed a multicenter, retrospective, case–control study of children with Hirschsprung disease (HD) who had undergone a pull-through procedure and were evaluated at a PCPLC member site between February 2017 and March 2020. The cohort with a history of postoperative HAEC was compared with that without postoperative episodes of HAEC to determine relevant associations with postoperative HAEC. Results One-hundred forty of 299 (46.8%) patients enrolled had a history of postoperative HAEC. Patients with a rectosigmoid transition zone had a lower association with postoperative HAEC as compared with those with a more proximal transition zone (odds ratio [OR]: 0.46, 95% confidence interval [CI]: 0.26, 0.84, p Conclusion Patients with a rectosigmoid transition zone have less postoperative HAEC compared with patients with a more proximal transition zone. Multi-institutional collection of clinical information in patients with HD may allow for the identification of additional risk factors for HAEC and afford the opportunity to improve care.

Introduction To our knowledge, there are no studies to date that have compared patients with isolated anorectal malformation (ARM) to patients with ARM and an associated genitourinary (GU) malformation despite a possible etiological difference between these two entities. We examined the differences in maternal and prenatal exposures and comorbidities between patients with isolated ARM and patients with ARM and associated GU malformations. Materials and methods A retrospective cohort study of children with ARM, enrolled in the Pediatric Colorectal and Pelvic Learning Consortium (PCPLC) between February 2017 and October 2019, was performed comparing those with isolated ARM to those with ARM and associated GU anomalies (GU +/- additional anomalies) as well as to those with ARM and a GU anomaly with no anomaly of any other system (GU-only). We compared the prevalence of prematurity, family history of colorectal disorders, as well as maternal and prenatal comorbidities and exposures between these two cohorts and the isolated ARM cohort. Results A total of 505 patients (117 with isolated ARM and 388 with ARM and associated GU anomalies) were enrolled. Of the 388 patients with ARM and associated GU anomalies, 48 had an ARM with a GU anomaly without an anomaly in any other system. There was an increased prevalence of premature births in the GU +/- additional anomalies cohort compared to the isolated ARM cohort (27 vs 14%, p=0.003). This difference was not seen in the GU-only cohort. There was no difference between the cohorts regarding prevalence of family history of ARM or maternal and prenatal comorbidities or exposures. Conclusions Patients with an ARM and an associated GU anomaly with or without other congenital anomalies are more likely to be born prematurely compared to patients with an isolated ARM. Parents of these children should be counseled on this increased risk.

Background Our goal is to determine short- and long-term outcomes of simple gastroschisis (SG) and complicated gastroschisis (CG) patients including quality of life (QoL) measures, surgical reoperation rates, and residual gastrointestinal symptom burden. Materials and methods Retrospective chart review of patients who underwent surgical repair of gastroschisis between January 1, 2009, and December 31, 2012, was performed at a quaternary children's hospital. Parent telephone surveys were conducted to collect information on subsequent operations and current health status as well as to assess QoL using two validated tools. Results Of 143 patients identified, 45 (31.5%) were reached and agreed to participate with a median follow-up age of 4.7 y. Although CG was associated with short-term outcomes such as longer length of stay, longer days to feeds, and higher complication rates, there were no major differences in long-term QoL outcomes when comparing SG and CG. Children with CG experienced abdominal pain/gas/diarrhea more often than those with SG and required more major abdominal procedures than those with SG (15% versus 0%, P = 0.009). Conclusions Despite worse short-term outcomes, presence of certain gastrointestinal symptoms, and need for more surgical interventions for patients with CG, and overall QoL scores were reassuringly similar to those with SG.

Short bowel syndrome (SBS) in neonates is an uncommon but highly morbid condition. As SBS survival increases, physiologic complications become more apparent. Few reports in the literature elucidate outcomes for adults with a pediatric history of SBS. We present a case report of a patient, born with complicated gastroschisis resulting in SBS at birth, who subsequently developed symptoms and pathologic changes of inflammatory bowel disease (IBD) as an adult. The patient lived from age 7, after a Bianchi intestinal lengthening procedure, to age 34 independent of parenteral nutrition (PN), but requiring hydration fluid via G-tube. He was then diagnosed with IBD, after presenting with weight loss, diarrhea, and malabsorption, which required resumption of PN and infliximab treatment. This report adds to a small body of the literature which points to a connection between SBS in neonates and subsequent diagnosis of IBD. Recent evidence suggests that SBS and IBD have shared features of mucosal immune dysfunction and altered intestinal microbiota. We review current treatment options for pediatric SBS as well as multidisciplinary and coordinated transition strategies. We conclude that there may be an etiologic connection between SBS and IBD and that this knowledge may impact outcomes and approaches to care.

Gastrointestinal duplication cysts are rare congenital malformations, with esophageal and gastric duplication cysts being among the rarest. We report an 8-week-old female who presented to the emergency department with failure to thrive and was subsequently found to have multiple gastric and esophageal duplication cysts that had ruptured intrathoracically and intra-abdominally. We describe the diagnosis and management of this patient who underwent successful resection of 4 gastrointestinal duplication cysts. This report emphasizes the unexpected, and sometimes relatively benign, presentations of gastrointestinal duplication cysts. To our knowledge, this is the first reported occurrence of multiple duplication cysts that independently ruptured thoracically and abdominally.

Although most children with Hirschsprung disease ultimately achieve functional and comfortable stooling, some will experience a variety of problems after pull-through surgery. The most common problems include soiling, obstructive symptoms, enterocolitis, and failure to thrive. The purpose of this guideline is to present a rational approach to the management of postoperative soiling in children with Hirschsprung disease. The American Pediatric Surgical Association Hirschsprung Disease Interest Group engaged in a literature review and group discussions. Expert consensus was then used to summarize the current state of knowledge regarding causes, methods of diagnosis, and treatment approaches to children with soiling symptoms following pull-through for Hirschsprung disease. Causes of soiling after pull-through are broadly categorized as abnormalities in sensation, abnormalities in sphincter control, and "pseudo-incontinence." A stepwise algorithm for the diagnosis and management of soiling after a pull-through for Hirschsprung disease is presented; it is our hope that this rational approach will facilitate treatment and optimize outcomes.

Background VACTERL association (as defined by 3 or more anomalies in any of the following systems: vertebral, anorectal, cardiac, trachea-esophageal, renal, or limb) is present in around a third of patients with anorectal malformations (ARM). In female ARM patients’ gynecologic anomalies are seen in conjunction with 1 in 5 rectovestibular and 1 in 20 rectoperineal fistulae. This study hypothesized that the presence of VACTERL association would predict an increased risk of gynecologic anomalies and this information will help to guide evaluation and management protocols. Methods This study is a cross-sectional, retrospective analysis from the prospectively-collected, multicenter registry of the Pediatric Colorectal and Pelvic Learning Consortium (PCPLC). Subjects with inflammatory bowel disease were not eligible for the PCPLC registry. The 316 female subjects with a perineal or vestibular fistula who were enrolled in the registry by January 14, 2020 were included in this study. The relationship of VACTERL association, ARM plus an anomaly in two or more VACTERL systems, with presence of a genital anomaly was evaluated with Fisher's exact test (Table 2). The relationship of each individual VACTERL system with presence of a genital anomaly was analogously assessed. P-values reported were based on a 2-sided alternative and considered significant when less than 0.05. Results 316 patients with rectoperineal (n=162, 51.3%) or rectovestibular (n=154, 48.7%) fistulae underwent VACTERL screening and gynecologic evaluation. 83 (26.3%) of patients with rectoperineal fistulae or rectovestibular fistulae had gynecologic anomalies. (Table 1). Among subjects with VACTERL association, 70.4% have a spine anomaly, 68.7% have a renal anomaly, and 70% have a cardiovascular anomaly. Genital anomalies were present in 40.9% vs. 17.9% of subjects with vs. without VACTERL association (p Conclusions Presence of VACTERL association in patients with rectoperineal or rectovestibular fistula correlates with an increased risk of gynecologic anomalies and should prompt early involvement of pediatric gynecology in their care.

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Patient-centered frameworks are an effective way to engage patients in treatment plans, strengthen adherence behaviors, and improve disease outcomes. These frameworks can also be applied in the design of mobile technology disease management applications. However, the utilization of these frameworks is rare and frequently overlooked in existing colorectal mobile health (mHealth) applications. The purpose of this study was to utilize a patient-centered framework to facilitate the development of a valid, appropriate, and feasible mHealth tool for pediatric patients and their caregivers. To inform application design and production, in-depth interviews were conducted with pediatric patients and their caregivers to capture management experiences, application preferences, and barriers and facilitators to application use. Patient ages ranged from 3 to 16. Six caregivers and 2 adolescent patients participated in the interviews. Patients and caregivers reported various management styles and desired an application that is not only user-friendly and customizable, but also able to facilitate communication and information sharing with other patients, caregivers, and providers. Older patients also wanted the application to give them more independence in managing their disease. Employing patient-centered frameworks is context-specific, but holds much promise at the intersection of mobile technology and healthcare. By incorporating pediatric patient experiences and viewpoints, we identified important components for inclusion in a mHealth surgical colorectal disease management application. Patients and caregivers wanted a mHealth application that was unique to their needs and easy to use. They suggested that the application include treatment tracking, note taking, and provider communication features.

Noniatrogenic neonatal gastric perforation is a rare and life-threatening condition whose etiology is often unclear. Interstitial cells of Cajal act as gastrointestinal pacemaker cells and express the proto-oncogene c-Kit. Six new cases were identified at our institution which presented with no mechanical, pharmacologic, or otherwise medical-related intervention prior to rupture. The number of interstitial cells of Cajal in nonnecrotic muscularis propria from five random high-power fields per specimen was compared using immunohistochemical stains for c-Kit. The authors show that a lack of interstitial cells of Cajal in the stomach musculature may be implicated in the development of noniatrogenic gastric perforation (p = 0.008). Further large-scale studies, including molecular and genetic analysis, may help to better understand this phenomenon.

Von Meyenburg complexes (VMCs), also known as bile duct hamartomas, are a part of a group of ductal plate malformations. They are typically present intrahepatically. In this case, we present to our knowledge the first report of an extra-hepatic VMC in the pediatric population. The patient presented as a 10-month-old infant with a weeklong history of progressive breathing difficulty. A chest radiograph was obtained, showing intestinal loops in the thoracic cavity consistent with a Morgagni's hernia, unrelated to his breathing difficulty. The patient then underwent an elective repair of his congenital diaphragmatic defect. During the operation, the bile duct hamartoma was found adherent to the accessory lobe of the liver, present to the left of the ligamentum teres.

The objective of this study was to assess whether a diet of ≥50% breast milk (BM) was associated with earlier transition off parenteral nutrition (PN) in neonates with gastrointestinal (GI) disorders.This retrospective study assessed enteral feeding outcomes of neonates with surgical GI disorders admitted within the first week of life to a single center between January 1, 2012 and August 10, 2015. Outcomes were assessed according to diet from the point of first enteral intake through 7 days of full enteral feeds. Diets were classified as 100%, ≥50%, or50% BM.One hundred sixty-three patients with an average gestational age of 36 weeks (range 28-40) and birthweight of 2570 g (range 1250-4900) were included. Significant differences in days to full enteral feeds between the 100% and50% BM groups were found (median 21 versus 32 days; p = 0.023). There were no significant differences between the 100% and ≥50% BM (p = 0.05) or ≥50% versus50% BM groups (p = 0.74). The 100% BM group had significantly fewer days on PN compared to the ≥50% BM group (median 21 versus 28.5 days, p = 0.034). Hospital length of stay was significantly shorter in the 100% BM group, which was discharged an average of 10 and 13.5 days sooner than the ≥50% and50% BM groups (p 0.05).Neonates with specific GI disorders who received a 100% BM diet were found to achieve earlier full enteral feeds, have shorter PN courses, and be discharged from the hospital significantly sooner than those who received diets that included formula.

Introduction: Multiple unilateral congenital diaphragmatic hernias (CDH) are extremely rare, described only five times in the medical literature. Concurrent ipsilateral Bochdalek and Morgagni hernias are rarer still with only two cases previously described. In all reported cases of multiple concurrent defects, the hernias were repaired in an open fashion, either via a thoracotomy or laparotomy with both of the two combined Bochdalek and Morgagni hernias repaired via laparotomy. Case Presentation: In this case report we have a 2-day-old who developed respiratory distress and on CT scan was found to have a congenital diaphragmatic hernia (CDH) or eventration. This patient is ideal for this case report because he meets a lot of the previously established criteria for minimally invasive repair of congenital diaphragmatic hernias - minimal respiratory compromise, no congenital heart defects - and he has synchronous defects which have very rarely been seen before. Here we present the first reported case of concurrent ipsilateral Bochdalek and Morgagni hernias repaired in a one-stage minimally invasive fashion, approaching the Bochdalek hernia thoracoscopically and the Morgagni laparoscopically. The patient had a quick recovery post-operatively and he continues to do well. Conclusions: From this experience, we argue that in the right circumstances a completely minimally invasive approach can be taken for synchronous congenital diaphragmatic hernias.

It is unclear if lymph node sampling in Wilms tumour, though critical for staging purposes, affects survival outcomes. The value of lymph node sampling in patients treated with neoadjuvant chemotherapy (NAC) is even more uncertain. We reviewed our institutional data to determine the impact of lymph node sampling on survival, as well as its role in the context of NAC. A total of 185 patients with Wilms tumour treated at our institution were included in this analysis. The number of nodes sampled (≤7, or7), lymph node status (unknown, negative, or positive), pathological stage, and use of neoadjuvant chemotherapy were analysed for survival outcomes. Covariates were evaluated with chi-square test or Fisher's exact test where appropriate. All analyses were performed using SAS 9.3 and R package version 2.15.2 with a significant level of 0.05. Median follow-up for all patients was 7.1 years. The number of lymph nodes sampled was significantly related to lymph node status (p0.001). Lymph node involvement portended worse overall survival after controlling for stage and histology. Patients treated with NAC had higher rates of 'unknown' lymph node status (p0.001) and worse overall survival than their counterparts (p=0.002); within this group, patients with 'unknown' lymph node status had significantly worse survival than those with negative or positive lymph node. Our data support the available evidence that sampling of more than seven lymph nodes is necessary for adequate staging of Wilms tumour. This is especially critical in patients treated with NAC, who had worse overall survival, likely due to understaging and undertreatment. These findings should be confirmed prospectively to provide proper guidelines to physicians caring for patients with Wilms tumour.

BACKGROUND: Previously, using imaging mass spectrometry (IMS), we discovered proteomic differences between Spitz nevi and Spitzoid melanomas. OBJECTIVE: We sought to determine whether IMS can assist in the classification of diagnostically challenging atypical Spitzoid neoplasms (ASN), to compare and correlate the IMS and histopathological diagnoses with clinical behavior. METHODS: We conducted a retrospective collaborative study involving centers from 11 countries and 11 US institutions analyzing 102 ASNs by IMS. Patients were divided into clinical groups 1 to 4 representing best to worst clinical behavior. The association among IMS findings, histopathological diagnoses, and clinical groups was assessed. RESULTS: There was a strong association between a diagnosis of Spitzoid melanoma by IMS and lesions categorized as clinical groups 2, 3, and 4 (recurrence of disease, metastases, or death) compared with clinical group 1 (no recurrence or metastasis beyond a sentinel node) (P < .0001). Older age and greater tumor thickness were strongly associated with poorer outcome (P = .01). CONCLUSIONS: IMS diagnosis of ASN better predicted clinical outcome than histopathology. Diagnosis of Spitzoid melanoma by IMS was strongly associated with aggressive clinical behavior. IMS analysis using a proteomic signature may improve the diagnosis and prediction of outcome/risk stratification for patients with ASN.

Hepatic pulmonary fusion (HPF) is characterized by a fibrous connection between the liver and lung tissue. We present two cases of hepatic pulmonary fusion diagnosed with right diaphragmatic hernia and a third case with Pentalogy of Cantrell exhibiting complete agenesis of the diaphragm and finger-like projections of liver adhered to the right lung. It has been proposed that this anomaly is secondary to developmental failure of the mesoderm between days 14-18 after conception and is attributed to diaphragmatic maldevelopment. Understanding the molecular-genetic basis of diaphragmatic hernias may shed light on this unusual presentation and explain why other cases show no fusion.

Ciliated hepatic foregut cysts (CHFCs) are rare congenital legions that arise from the embryonic foregut. The cysts are formed during fetal development by evagination from their respective portions of the foregut, and are characterized by a ciliated epithelial lining. Approximately 100 cases of CHFC have been reported, of which only 13 were in children. Although CHFC is typically benign, malignant transformation to squamous cell carcinoma (SCC) has been reported in 3 cases. Survival rate after progression to malignancy is poor, as SCC in this setting is biologically aggressive. We present 4 new cases of CHFC in children between 5 months and 17 years old. Our cases are unusual, as some of the cysts exhibit multilocularity and biliary communication, and 2 of our patients were diagnosed under the age of 1. Additionally, 1 of the cysts was 19.3 cm in diameter, making it the largest reported CHFC to our knowledge. Ciliated hepatic foregut cysts should be included in the differential diagnosis of hepatic lesions.

Intestinal atresias are a common cause of newborn bowel obstruction (Dalla Vecchia LK, Grosfeld JL, West KW, et al, Intestinal atresia and stenosis: a 25-year experience with 277 cases. Arch Surg 1998; 133[5]:490-496). Hereditary multiple intestinal atresias, first reported by Guttman et al in 1973, is the rarest form of multiple atresias (Guttman FM, Braun P, Garance PH, et al, Multiple atresias and a new syndrome of hereditary multiple atresias involving the gastrointestinal tract from stomach to rectum. J Pediatr Surg 1973;8:633-640; Bass J, Pyloric atresia associated with multiple intestinal atresias and immune deficiency. J Pediatr Surg 2002;37:941-942.). It has been proposed to be autosomal recessive, to involve atresias in a variable combination of sites from stomach to rectum, and to be universally fatal (Bilodeau A, Prasil P, Cloutier R, et al, Hereditary multiple intestinal atresia: thirty years later. J Pediatr Surg 2004;39:726-730; Moreno LA, Gottrand F, Turck D, et al, Severe combined immunodeficiency syndrome associated with autosomal recessive familial multiple gastrointestinal atresias: study of a family. Am J Med Genet 1990;37:143-146). Patients have significant intestinal dysfunction and unrelenting sepsis stemming from a poorly defined, severe immunologic defect. Our case report presents 2 full siblings to nonconsanguineous parents with pyloric atresia, multiple small bowel and colonic atresias, and severe immune dysfunction. Care was withdrawn within 3 months of life on both siblings after multiple bouts of sepsis. Data suggest that the immune defect may not be primary, but in fact be secondary to intestinal dysfunction. Although the subjects in this article ultimately had fatal outcomes, a comprehensive immunologic/physiologic picture is presented in hopes of furthering the understanding of this grave disease.

A strategy for producing high-level hematopoietic chimerism after non-myeloablative conditioning has been established in the rhesus macaque. This strategy relies on hematopoietic stem cell transplantation after induction with a non-myeloablative dose of busulfan and blockade of the IL2-receptor in the setting of mTOR inhibition with sirolimus and combined CD28/CD154 costimulation blockade. Hematopoietic stem cells derived from bone marrow and leukopheresis products both were found to be successful in inducing high-level chimerism. Mean peripheral blood peak donor chimerism was 81% with a median chimerism duration of 145 days. Additional immune modulation strategies, such as pre-transplant CD8 depletion, donor-specific transfusion, recipient thymectomy or peritransplant deoxyspergualin treatment did not improve the level or durability of chimerism. Recipient immunologic assessment suggested that chimerism occurred amidst donor-specific down-regulation of alloreactive T cells, and the reappearance of vigorous T-mediated alloreactivity accompanied rejection of the transplants. Furthermore, viral reactivation constituted a significant transplant-related toxicity and may have negatively impacted the ability to achieve indefinite survival of transplanted stem cells. Nevertheless, this chimerism-induction regimen induced amongst the longest-lived stem cell chimerism reported to date for non-human primates and thus represents a platform upon which to evaluate emerging tolerance-induction strategies.

Anti- N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is a potentially fatal neurologic syndrome in which patients present with a spectrum of central nervous system deficits. Sixty percent of the cases can be attributed to the presence of tumors, most often ovarian teratomas. This report examines 6 pediatric patients who presented with neurologic deficits associated with the presence of such tumors. These cases illustrate a perplexing phenomenon, where benign teratomas could have a possible association with anti-NMDAR encephalitis. The purpose of this study was to compare the histology and immunohistochemistry of tumors associated with this syndrome to ovarian teratomas found in patients presenting with no neurologic symptoms. After obtaining institutional review board approval, 57 cases of ovarian teratomas were identified at our institution over 12 years. Six patients were identified with anti-NMDAR encephalitis. A panel of immunostains, including S100, GFAP, MAP2, and NeuN was applied to patients' tumor sections as well as the 6 controls from age-matched patients. No qualitative histologic or immunohistochemical differences were seen between the study cases and control group. Because no qualitative differences were identified between the study cases and the control group, testing of paired serum and cerebrospinal fluid remains the best method for diagnosis of anti-NMDAR encephalitis. Tumor banking with molecular analysis of ovarian teratomas, including whole-genome sequencing and comparative genomic hybridization between ovarian tissue saved from patients with and without anti-NMDAR encephalitis, is necessary to fully understand the etiopathogenesis of anti-NMDAR encephalitis.

Bariatric surgery has become a standard of care for the treatment of severely obese adults who meet National Institutes of Health criteria. Unfortunately, there is a need for weight loss surgery in adolescents. Criteria developed for adolescents are generally more restrictive than those for adults due to concerns about the ability of children to consent for life-altering surgery and the lack of long-term results. Several preliminary series have reported adolescent bariatric procedures with promising results. The two primary bariatric procedures performed on adolescents are Roux-en-Y gastric bypass (RYGB) and adjustable gastric banding (AGB). Each procedure has its advantages and disadvantages. RYGB has the longest follow-up results and is considered the "gold standard." AGB has promising results, is reversible, and can be performed with less morbidity and mortality.

In recent years, reagents have been developed that specifically target signals critical for effective T cell activation and function. Manipulation of the CD28/CD80/86 and CD40/CD154 pathways has exhibited extraordinary efficacy, particularly when the pathways are blocked simultaneously. Despite the reported efficacy of anti-CD154 in rodents and higher models, its future clinical use is uncertain due to reported thromboembolic events in clinical trials. To circumvent this potential complication, we developed and evaluated a chimeric Ab targeting CD40 (Chi220, BMS-224819) as an alternative to CD154. Although Chi220 blocks CD154 binding, it also possesses partial agonist properties and weak stimulatory potential. The anti-CD40 was tested alone and in combination with a rationally designed, high affinity variant of CTLA4-Ig, LEA29Y (belatacept), in a nonhuman primate model of islet transplantation. Although either agent alone only modestly prolonged islet survival (Chi220 alone: 14, 16, and 84 days; LEA29Y alone: 58 and 60 days), their combination (LEA29Y and Chi220) dramatically facilitated long term survival (237, 237, 220, >185, and 172 days). We found that the effects of Chi220 treatment were not mediated solely through deletion of CD20-bearing cells and that the combined therapy did not significantly impair established antiviral immunity.

The establishment of immune tolerance to self antigen expressed exclusively in the periphery is a crucial yet incompletely understood feature of the immune system. A dominant concept of peripheral tolerance has been that exposure of T cells to signal one, the TCR-MHC interaction, in the absence of signal two, or costimulation, is a major mechanism of peripheral tolerance. This model suggests that any cell type that expresses MHC-peptide complexes, be they of self or foreign origin, should have the capacity to tolerize antigen-specific T cells when critical costimulatory interactions are interrupted. However, a spectrum of responses, from permanent engraftment to rapid rejection, has been observed in various transplantation models utilizing costimulatory blockade. Therefore we undertook a series experiments to directly assess the tolerogenic potential of donor hematopoietic and parenchymal cells. We find that allogeneic tissues differ profoundly in their ability to promote peripheral tolerance concurrent with combined blockade of B7-CD28 and CD40-CD40L pathways. Non-vascularized and vascularized parenchymal grafts as well as donor-specific transfusions promote varying degrees of donor-specific hyporesponsiveness, but fail to induce donor-reactive T-cell deletion; whereas establishment of stable hematopoietic chimerism promotes specific tolerance mediated by deletion of donor-reactive cells in the periphery.

Background A plethora of studies have described repair of pectus deformities in children, but only few reports have described this repair in adults. The purpose of this study was to review our 30-year experience with surgical repair of pectus deformities in adults. Methods A retrospective review of all adult patients (> 16 years old) who underwent repair of congenital pectus deformities from 1971 through 2001. Results There were 77 patients, 64 men and 13 women. Sixty-eight patients underwent surgery for pectus excavatum and 9 for pectus carinatum; median age was 22 years old (range, 16 to 68 years old). Indication for repair was medical concerns in all patients. Preoperative symptoms were dyspnea on exertion in 43 patients, shortness of breath at rest in 22 patients, chest pain in 8 patients, and palpitations in 8 patients. Preoperative electrocardiogram findings included right bundle branch block in 9 patients, sinus bradycardia in 8 patients, left atrial enlargement in 6 patients, and right atrial dilatation in 5 patients. Patterns of the pectus defect were symmetric and localized in 29 patients, symmetric and diffuse in 21, asymmetric and localized in 18, and asymmetric and diffuse in 9 patients. Intraoperative classifications were severe in 38 patients, moderate in 33 patients, and mild in 6 patients. There were no operative deaths. Complications occurred in 11 patients (14.3%). Mean hospital stay was 4 days (range, 2 to 8 days). Mean follow-up was 12 ± 7 years (range, 4 months old to 24 years old); 1 patient (1.3%) required reoperation for recurrent pectus excavatum. Patient satisfaction and relief of medical symptoms was excellent in 70 patients (90.9%), good in 6 patients, and fair in 1 patient. Conclusions Repair of congenital defects of the sternum in adults can be performed safely with low morbidity and no mortality. Long-term results are excellent with requirement for reoperation rare.

T-cell costimulatory blockade has emerged as an effective strategy to prevent allograft rejection in experimental models. We and others have reported that the beneficial effects of costimulation blockade can be negated when combined with certain immunosuppressants. The current study evaluates the compatibility of various immunosuppressive agents in a costimulation blockade-based, mixed chimerism tolerance protocol. The addition of conventional agents, including calcineurin inhibitors, did not interfere with tolerance induction. All mice developed multilineage macrochimerism and accepted donor allografts. Analysis of specific T-cell receptor utilization demonstrated selective deletion of donor-reactive T cells. Challenge with donor and third-party allografts confirmed donor-specific tolerance. Clinical introduction of costimulation blockade-based strategies will likely incorporate currently approved immunosuppressive agents. While it has been reported that certain conventional agents are detrimental to costimulation blockade-based strategies, our results suggest that these agents could safely be combined in clinical trials when used as part of a nonmyelosuppressive, mixed chimerism-based tolerance strategy.

Pediatric cervicovaginal clear cell adenocarcinoma (CCA) is rare but continues to occur in the postdiethylstilbestrol era. Ideal management is unclear. We report a case of locally advanced, node-negative CCA in a 14-year-old girl without a history of diethylstilbestrol exposure. The patient's disease was FIGO stage IIIA, involving the cervix, vagina, and parametrium. She was treated with concurrent cisplatin and external beam radiation, followed by interstitial low-dose rate brachytherapy. The patient has no evidence of disease after 2 years of follow-up. These findings support the use of definitive chemoradiation as a treatment option for adolescents with locally advanced CCA.

PURPOSE: We wished to determine whether virally- induced endothelial tumors are rejected by CD4 and CD8 lymphocytes, and whether there are differences in requirements for costimulation in the rejection of these tumors by lymphocyte subsets. EXPERIMENTAL DESIGN: We have developed a model of endothelial tumorigenesis through the sequential introduction of SV40 large T antigen and oncogenic H-ras into endothelial cells. These cells (SVR cells) form highly aggressive angiosarcomas in immunocompromised mice, but do not grow in syngeneic C57BL/6 mice. Using both acute blockade with systemic administration of antibodies and mice genetically deficient in the costimulatory molecules CD28, CD40, and CD40L, we have delineated the requirements of costimulation required to reject this virally-induced endothelial tumor. RESULTS: Control of SVR angiosarcoma is mediated through T lymphocytes, and both CD4 and CD8 lymphocytes are capable of controlling SVR angiosarcoma growth in vivo. Mice genetically deficient in CD28, CD40, and CD40L were able to reject SVR tumors, but depletion of these mice of CD8, but not CD4 cells led to rapid tumor growth. This data suggests that CD4 mediated rejection has a greater dependence of costimulation than CD8 mediated rejection. Surprisingly, acute depletion of costimulatory molecules in immunocompetent C57BL/6 mice led to rapid tumor growth. CONCLUSIONS: Significant differences exist in the immune status of mice acutely depleted of costimulatory molecules versus genetically deficient mice. Our results suggest that acute depletion is more immunosuppressive than genetic depletion. Humans who undergo costimulatory blockade may require periodic surveillance for virally-induced tumors.

The morbidity and mortality associated with sickle cell disease (SCD) is caused by hemolytic anemia, vaso-occlusion, and progressive multiorgan damage. Bone marrow transplantation (BMT) is currently the only curative therapy; however, toxic myeloablative preconditioning and barriers to allotransplantation limit this therapy to children with major SCD complications and HLA-matched donors. In trials of myeloablative BMT designed to yield total marrow replacement with donor stem cells, a subset of patients developed mixed chimerism. Importantly, these patients showed resolution of SCD complications. This implies that less toxic preparative regimens, purposefully yielding mixed chimerism after transplantation, may be sufficient to cure SCD without the risks of myeloablation. To rigorously test this hypothesis, we used a murine model for SCD to investigate whether nonmyeloablative preconditioning coupled with tolerance induction could intentionally create mixed chimerism and a clinical cure. We applied a well-tolerated, nonirradiation-based, allogeneic transplantation protocol using nonmyeloablative preconditioning (low-dose busulfan) and costimulation blockade (CTLA4-Ig and anti-CD40L) to produce mixed chimerism and transplantation tolerance to fully major histocompatibility complex–mismatched donor marrow. Chimeric mice were phenotypically cured of SCD and had normal RBC morphology and hematologic indices (hemoglobin, hematocrit, reticulocyte, and white blood cell counts) without evidence of graft versus host disease. Importantly, they also showed normalization of characteristic spleen and kidney pathology. These experiments demonstrate the ability to produce a phenotypic cure for murine SCD using a nonmyeloablative protocol with fully histocompatibility complex–mismatched donors. They suggest a future treatment strategy for human SCD patients that reduces the toxicity of conventional BMT and expands the use of allotransplantation to non–HLA-matched donors.

Recent success using a steroid-free immunosuppressive regimen has renewed enthusiasm for the use of islet transplantation to treat diabetes. Toxicities associated with the continued use of a calcineurin inhibitor may limit the wide-spread application of this therapy. Biological agents that block key T-cell costimulatory signals, in particular the CD28 pathway, have demonstrated extraordinary promise in animal models. LEA29Y (BMS-224818), a mutant CTLA4-Ig molecule with increased binding activity, was evaluated for its potential to replace tacrolimus and protect allogeneic islets in a preclinical primate model. Animals received either the base immunosuppression regimen (rapamycin and anti–IL-2R monoclonal antibody [mAb]) or the base immunosuppression and LEA29Y. Animals receiving the LEA29Y/rapamycin/anti–IL-2R regimen (n = 5) had significantly prolonged islet allograft survival (204, 190, 216, 56, and >220 days). In contrast, those animals receiving the base regimen alone (n = 2) quickly rejected the transplanted islets at 1 week (both at 7 days). The LEA29Y-based regimen prevented the priming of anti-donor T- and B-cell responses, as detected by interferon-γ enzyme-linked immunospot and allo-antibody production, respectively. The results of this study suggest that LEA29Y is a potent immunosuppressant that can effectively prevent rejection in a steroid-free immunosuppressive protocol and produce marked prolongation of islet allograft survival in a preclinical model.

Blockade of the CD40 and CD28 costimulatory pathways significantly prolongs allograft survival; however, certain strains of mice (i.e., C57BL/6) are relatively resistant to the effects of combined CD40/CD28 blockade. We have previously shown that the costimulation blockade-resistant phenotype can be attributed to a subset of CD8+ T cells and is independent of CD4+ T cell-mediated help. Here we explore the role of the IL-2 pathway in this process using mAbs against the high affinity IL-2R, CD25, and IL-2 in prolonging skin allograft survival in mice receiving combined CD40/CD28 blockade. We have also investigated the effects of treatment on effector function by assessment of cytotoxicity and the generation of IFN-γ-producing cells in response to allogeneic stimulators as well as proliferation in an in vivo graft-vs-host disease model. We find that additional blockade of either CD25 or IL-2 significantly extends allograft survival beyond that in mice receiving costimulation blockade alone. This correlates with diminished frequencies of IFN-γ-producing allospecific T cells and reduced CTL activity. Anti-CD25 therapy also synergizes with CD40/CD28 blockade in suppressing proliferative responses. Interestingly, depletion of CD4+ T cells, but not CD8+ cells, prevents prolongation in allograft survival, suggesting an IL-2-independent role for regulation in extended survival.

Purpose Controversy remains regarding the management of the asymptomatic heterotaxy syndrome (HS) patient with suspected intestinal rotational abnormalities. We evaluated the outcomes for our HS population to identify frequency of malrotation and identify characteristics of children who might benefit from expectant management. Methods After IRB approval, a retrospective review of all patients treated for HS at a large tertiary care children's hospital between January 2008 and June 2012 was performed. For the purpose of this paper, malrotation was defined as an operative note that described the presence of Ladd's bands and a narrow mesentery. Results Thirty-eight patients with HS were identified, including 18 who underwent abdominal exploration. Left atrial isomerisation (LAI) was identified in 13 individuals, and right atrial isomerisation (RAI) was noted in 25. The rate of surgical intervention did not vary between the 2 groups (54%). Malrotation was found in 8 patients: one with LAI and 7 with RAI. This difference in incidence was statistically significant (p=0.04). Conclusion These data suggest that the direction of atrial isomerisation influences the likelihood of true malrotation, where RAI patients are more likely to be malrotated. Given the inherent risk of surgery on this medically fragile patient population, surgeons should consider expectant management for asymptomatic LAI patients.

Background. Blockade of the CD40 and CD28 pathways is a powerful strategy to inhibit CD4-mediated alloimmune responses. In this study, we examine the relative roles of the CD40 and CD28 pathways on CD4-mediated allograft rejection responses, and further characterize the role of these pathways on CD4 + T-cell activation, priming for cytokine production, and cell proliferation in response to alloantigen in vivo. Methods. BALB/c skin allografts were transplanted onto C57BL/6 Rag 1-/- recipients reconstituted with CD4 cells from CD28-/- or CD40L-/- donors. The popliteal lymph node assay was used to study the role of these pathways on CD4-cell activation and priming in vivo. To investigate the role of CD40 and CD28 blockade on CD4-cell proliferation, the fluorescein dye carboxyfluorescein diacetate succinimidyl ester was used. We performed heterotopic cardiac transplantation using CD40-/- mice to evaluate the role of CD40 on donor versus recipient cells in CD4-mediated rejection. Results. B6 Rag 1-/- recipients reconstituted with CD28-/- CD4 + T cells acutely rejected allografts (median survival time 15 days), whereas recipients reconstituted with CD40L-/- CD4 + T cells had significantly prolonged survival of BALB/c skin grafts (MST 71 days). CD40L blockade was equivalent to or inferior to CD28 blockade in inhibition of in vivo CD4-cell activation, priming for cytokine production, and proliferation responses to alloantigen. BALB/c recipients depleted of CD8 cells promptly rejected donor B6 CD40-/- cardiac allografts, whereas B6 CD40-/- recipients depleted of CD8 cells had significantly prolonged survival of BALB/c wild-type cardiac allografts. Conclusions. The CD40/CD40L pathway, but not the CD28/B7 pathway, is critical for CD4-mediated rejection responses, however, the responsible mechanisms remain unclear.