Clinical outcomes of splenectomy in children: report of the splenectomy in congenital hemolytic anemia registry.

The outcomes of children with congenital hemolytic anemia (CHA) undergoing total splenectomy (TS) or partial splenectomy (PS) remain unclear. In this study, we collected data from 100 children with CHA who underwent TS or PS from 2005 to 2013 at 16 sites in the Splenectomy in Congenital Hemolytic Anemia (SICHA) consortium using a patient registry. We analyzed demographics and baseline clinical status, operative details, and outcomes at 4, 24, and 52 weeks after surgery. Results were summarized as hematologic outcomes, short-term adverse events (AEs) (≤30 days after surgery), and long-term AEs (31-365 days after surgery). For children with hereditary spherocytosis, after surgery there was an increase in hemoglobin (baseline 10.1 ± 1.8 g/dl, 52 week 12.8 ± 1.6 g/dl; mean ± SD), decrease in reticulocyte and bilirubin as well as control of symptoms. Children with sickle cell disease had control of clinical symptoms after surgery, but had no change in hematologic parameters. There was an 11% rate of short-term AEs and 11% rate of long-term AEs. As we accumulate more subjects and longer follow-up, use of a patient registry should enhance our capacity for clinical trials and engage all stakeholders in the decision-making process.

Pressure ulcers in the pediatric patient.

PURPOSE OF REVIEW: In contrast to adult literature, data for pressure ulcers in children is limited. Incidence and prevalence of this skin integrity issue in pediatric hospitals is still widely unknown, perhaps because increased awareness and prevention of the phenomenon have been slow to develop. Moreover, identification of at-risk patients is lacking, and current guidelines and interventions to prevent skin breakdown are those that have been adapted from adult care and are not supported by evidence-based data in children. RECENT FINDINGS: Awareness and prevention of pressure ulcers in the pediatric acute care setting are becoming a priority. In 2008, the Centers for Medicare and Medicaid Services listed certain hospital acquired conditions for which facilities would no longer be additionally reimbursed. A pressure ulcer, stage III or higher, is included in that list and referred to as a 'never event' as it is a condition that could be reasonably prevented by use of evidence-based guidelines. SUMMARY: Pediatric pressure ulcers are a serious and largely preventable condition. Increased awareness, and accurate and timely assessment to recognize at-risk children, can lead to pressure ulcer prevention. More studies are needed to better define risk factors and effective prevention of pediatric pressure ulcers.

Hematologic outcomes after total splenectomy and partial splenectomy for congenital hemolytic anemia.

PURPOSE: The purpose of this study was to define the hematologic response to total splenectomy (TS) or partial splenectomy (PS) in children with hereditary spherocytosis (HS) or sickle cell disease (SCD). METHODS: The Splenectomy in Congenital Hemolytic Anemia (SICHA) consortium registry collected hematologic outcomes of children with CHA undergoing TS or PS to 1 year after surgery. Using random effects mixed modeling, we evaluated the association of operative type with change in hemoglobin, reticulocyte counts, and bilirubin. We also compared laparoscopic to open splenectomy. RESULTS: The analysis included 130 children, with 62.3% (n=81) undergoing TS. For children with HS, all hematologic measures improved after TS, including a 4.1g/dl increase in hemoglobin. Hematologic parameters also improved after PS, although the response was less robust (hemoglobin increase 2.4 g/dl, p<0.001). For children with SCD, there was no change in hemoglobin. Laparoscopy was not associated with differences in hematologic outcomes compared to open. TS and laparoscopy were associated with shorter length of stay. CONCLUSION: Children with HS have an excellent hematologic response after TS or PS, although the hematologic response is more robust following TS. Children with SCD have smaller changes in their hematologic parameters. These data offer guidance to families and clinicians considering TS or PS.

Management of Traumatic Wounds and a Novel Approach to Delivering Wound Care in Children.

Significance: The costs and morbidity of pediatric traumatic wounds are not well known. The literature lacks a comprehensive review of the volume, management, and outcomes of children sustaining soft tissue injury. We briefly review the existing literature for traumatic wounds such as open fractures and burns. Such injuries require dedicated wound care and we propose a novel approach for more efficient and more effective delivery of dedicated pediatric wound care. Recent Advances: New pediatric literature is emerging regarding the long-term effects of wound care pain in traumatic injuries-especially burns. A variety of wound dressings and alternative management techniques exist and are geared toward reducing wound care pain. Our institution utilizes a unique model to provide adequate sedation and pain control through a dedicated pediatric wound care unit. We believe that this model reduces the cost of wound care by decreasing emergency department and operating room visits as well as hospital length of stay. Critical Issues: First, medical costs related to pediatric traumatic wound care are not insignificant. The need for adequate pain control and sedation in children with complex wounds is traditionally managed with operating room intervention. Afterward, added costs can be from a hospital stay for ongoing acute wound management. Second, morbidities of complex traumatic wounds are shown to be related to the acute wound care received. Future Directions: Further guidelines are needed to determine the most effective and efficient care of complex traumatic soft tissue injuries in the pediatric population.

Polyps in children.

Children with polyps usually present with bleeding or pain. Most pediatric intestinal polyps are sporadic and are not associated with malignancy. Polyposis syndromes are also well described in children. Peutz-Jeghers syndrome is the most common hamartomatous polyposis condition. Although the polyps are not thought to be premalignant in most patients, there is an increased risk of other cancers. Familial adenomatous polyposis is also seen in childhood and is associated with a very high risk of malignant transformation as well as extracolonic adenomas and malignancy. The diagnosis and management of sporadic juvenile polyps, Peutz-Jeghers syndrome, and familial adenomatous polyposis, as well as rarer conditions associated with intestinal polyps are reviewed in this article.

Resection-induced intestinal adaptation and the role of enteric smooth muscle.

BACKGROUND: Intestinal adaptation after massive small bowel resection (SBR) involves all layers of the bowel wall. Most prior work has focused on changes that occur in the intestinal mucosa. However, the contribution of the underlying intestinal smooth muscle (ISM) to the overall adaptation response remains unclear. METHODS: Male C57BL/6 or waved-2 (diminished activity of the epidermal growth factor receptor) mice underwent a 50% proximal SBR or sham operation, and the remnant ileum was harvested 3, 7, and 28 days. Markers of adaptation (villus height, bowel length, circumference, and ISM thickness) and ISM proliferation were recorded. Contractility was measured by attaching the distal ileum to strain gauge transducers and exposed to varying doses of carbachol. RESULTS: Intestinal smooth muscle thickness was unchanged at any given time-point after resection; however, the bowel caliber and length were increased, and augmented rates of ISM proliferation were identified. Contractility was increased at 7 days after SBR. Waved-2 mice demonstrated minimal proliferation or intestinal lengthening in response to SBR. CONCLUSION: Compared with resection-induced thickening of the mucosa, proliferative changes in the ISM are unique and primarily affect bowel caliber, length, and contractility. Epidermal growth factor receptor signaling appears to play a significant role in adaptation of the ISM cellular compartment.

Epidermal growth factor receptor-directed enterocyte proliferation does not induce Wnt pathway transcription.

BACKGROUND: Epidermal growth factor receptor (EGFR) stimulation enhances intestinal adaptation after massive small bowel resection (SBR), measured by taller villi, deeper crypts, and augmented enterocyte proliferation. Min mice with constitutively active beta-catenin signaling demonstrate enhanced villus growth after SBR, suggesting a role for the Wnt pathway during adaptation. Because there is crosstalk between EGFR signaling and the Wnt pathway, we hypothesized that beta-catenin is modulated by EGFR-induced enterocyte proliferation. METHODS: Rat intestinal epithelial cells were stimulated with EGF and cytoplasmic to nuclear trafficking of beta-catenin was measured. Beta-catenin-directed transcription was also tested via transfection with a TOP/FOP luciferase reporter. Downstream transcriptional target expression was measured in murine intestine after SBR. RESULTS: Epidermal growth factor-treated rat intestinal epithelial cells exhibited increased proliferation compared to serum-deficient cells in the face of no detectable accumulation of nuclear beta-catenin. The luciferase assay results showed minimal transcription activity in response to EGF. In vivo experiments revealed no significant difference in expression of beta-catenin targeted genes in crypt enterocytes after SBR. CONCLUSIONS: The mechanism for EGFR-induced proliferation of enterocytes does not appear to involve a transcriptional role for beta-catenin. The effects of EGFR signaling on beta-catenin-mediated cell adhesion remain to be investigated.

Epidermal growth factor receptor-mediated proliferation of enterocytes requires p21waf1/cip1 expression.

BACKGROUND & AIMS: Epidermal growth factor receptor (EGFR)-mediated increase in enterocyte proliferation following massive resection is a major mechanism by which the small intestine adapts to the loss of its mucosal surface area. In addition, expression of the cyclin-dependent kinase inhibitor p21(waf1/cip1) is required for resection-induced enterocyte proliferation. This study sought to establish a mechanistic link between EGFR-mediated intestinal epithelial cell proliferation and p21(waf1/cip1) expression. METHODS: EGF was used to stimulate IEC-6 and HCA-7 cells. P21(waf1/cip1) messenger RNA (mRNA) and protein expression were measured by real-time polymerase chain reaction and Western blot, respectively. P21(waf1/cip1) promoter studies were performed using p21(waf1/cip1) promoter-driven luciferase assay. Pharmacologic inhibitors of PI3-kinase and mitogen activated protein kinase (MAPK) were used to block these pathways downstream of the activated EGFR. Constitutively active Ras, Raf, or MEK-1 constructs were transfected into cells for overexpression studies. Cell proliferation was measured by bromodeoxyuridine incorporation following p21(waf1/cip1) silencing with RNAi. Finally, Cyclin D(1)/Cdk interaction was evaluated by immunoprecipitation. RESULTS: EGFR activation in intestinal epithelial cells induced the expression of p21(waf1/cip1) mRNA and protein This event was transcriptionally regulated via a 50-bp segment of the p21(waf1/cip1) promoter as a result of MAPK activation. Exogenous EGF failed to induce proliferation in p21(waf1/cip1)-silenced cells and adaptive proliferation after intestinal resection in p21(waf1/cip1)-null mice. Functionally, p21(waf1/cip1) up-regulation was required for stabilizing Cyclin D/Cdk 4 complexes and intestinal cell proliferation. CONCLUSIONS: EGFR-mediated induction of enterocyte proliferation requires MAPK-dependent increase in p21(waf1/cip1) expression in intestinal epithelial cells. These studies elucidate an important mechanism for resection-induced enterocyte proliferation during intestinal adaptation.

Roles for p21waf1/cip1 and p27kip1 during the adaptation response to massive intestinal resection.

The magnitude of gut adaptation is a decisive factor in determining whether patients are able to live independent of parenteral nutrition after massive small bowel loss. We previously established that the cyclin-dependent kinase inhibitor (CDKI) p21(waf1/cip1) is necessary for enterocyte proliferation and a normal adaptation response. In the present study, we have further elucidated the role of this CDKI in the context of p27(kip1), another member of the Cip/Kip CDKI family. Small bowel resections (SBRs) or sham operations were performed in control (C57/BL6), p21(waf1/cip1)-null, p27(kip1)-null, and p21(waf1/cip1)/p27(kip1) double-null mice. Morphological (villus height/crypt depth) alterations in the mucosa, the kinetics of enterocyte turnover (rates of enterocyte proliferation and apoptosis), and the protein expression of various cell cycle-regulatory proteins were recorded at various postoperative times. Enterocyte compartment-specific mRNA expression was investigated using laser capture microdissection. Resection-induced adaptation in control mice coincided with increased protein expression of p21(waf1/cip1) and decreased p27(kip1) within 3 days postoperatively. Identical changes in mRNA expression were detected in crypt but not in villus enterocytes. Adaptation occurred normally in control and p27(kip1)-null mice; however, mice deficient in both p21(waf1/cip1) and p27(kip1) failed to increase baseline rates of enterocyte proliferation and adaptation. The expression of p21(waf1/cip1) protein and mRNA in the proliferative crypt compartment is necessary for resection-induced enterocyte proliferation and adaptation. The finding that deficient expression of p27(kip1) does not affect adaptation suggests that these similar CDKI family members display distinctive cellular functions during the complex process of intestinal adaptation.

Absent STAT-1 expression perturbs adaptation and apoptosis after massive intestinal resection.

BACKGROUND: We have previously established the significance of epidermal growth factor receptor (EGFR) activity and the cyclin-dependent kinase inhibitor p21waf1/cip1 (p21) for the adaptive response of the intestine to massive small bowel resection (SBR). In this study, we tested the role of the signal transducer and activator of transcription 1 (STAT-1) as this transcription factor is activated by the EGFR and known to induce p21 expression. METHODS: Control (n = 40; C57/Bl6) and STAT-1-null mice (n = 40) underwent 50% proximal SBR or sham operation. After 3 days, the remnant ileum was harvested and the villus and crypt morphology was measured along with changes in rates of enterocyte proliferation and apoptosis. RESULTS: The magnitude of resection-induced adaptation was greater in STAT-1-null animals as verified by taller villi and deeper crypts. The expected increase in enterocyte apoptosis did not occur after SBR in the background of STAT-1 deficiency. Western blotting revealed elevated expression of p21 protein in both STAT-1-null and controls after SBR. CONCLUSION: Increased p21 expression after SBR in the absence of STAT-1 suggests an alternate mechanism for resection-induced regulation of p21. Enhanced adaptation in STAT-1-null animals suggests that this transcription factor serves an inhibitor to the process of adaptation, perhaps via regulation of enterocyte apoptosis.