The Childrens Hospital Of Philadelphia

Philadelphia, PA, United States

The Childrens Hospital Of Philadelphia

Philadelphia, PA, United States
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BACKGROUND—: Cardiovascular disease in breast cancer patients is of growing concern. The longitudinal effects of commonly used therapies, including doxorubicin and trastuzumab, on cardiac remodeling and function remain unknown in this population. We sought to define the changes in echocardiographic parameters of structure, function, and ventricular-arterial (VA) coupling, and their associations with left ventricular ejection fraction (LVEF) and heart failure (HF) symptoms. METHODS—: In a longitudinal prospective cohort study of 277 breast cancer participants receiving doxorubicin (Dox), trastuzumab (Tras), or both (Dox+Tras), we obtained 1,249 echocardiograms over a median followup of 2.0 (interquartile range 1.0,3.0) years. LV structure; diastolic and contractile function; and VA coupling measures were quantified in a core laboratory blinded to participant characteristics. We evaluated changes in echocardiographic parameters over time, and used repeated-measures regression models to define their association with LVEF decline and recovery. Linear regression models defined the association between early changes in these parameters and subsequent changes in LVEF and HF symptoms. RESULTS—: Overall, 177 (64%) received Dox; 51 (18%) Tras; and 49 (18%) Dox+Tras. With Dox, there was a sustained, modest decrease in LVEF over the followup duration (1-year change in LVEF -3.6%, 95% Confidence Interval [CI] -4.4%,-2.8%; 3-year change -3.8%, 95%CI -5.1%, -2.5%). With Tras, a similar LVEF decline was observed at 1 year (-4.5%, 95%CI -6.0%,-2.9%) and 3 years (-2.8%, 95%CI -5.3,-0.4%). Participants receiving Dox+Tras demonstrated the greatest declines at 1 year (-6.6%, 95%CI -8.2,-5.0%), with partial recovery at 3 years (-2.8%, 95%CI -4.8,-0.8%). LVEF declines and recovery were associated primarily with changes in systolic volumes; longitudinal and circumferential strain; and VA coupling indices effective arterial elastance (Ea) and the coupling ratio Ea/Eessb, without evidence for effect modification across therapies. Early changes in volumes, strain, and Ea/Eessb at 4 to 6 months were associated with 1- and 2-year LVEF changes. Similarly, early changes in strain and Ea were associated with worsening HF symptoms at 1 year. CONCLUSIONS—: Doxorubicin and trastuzumab resulted in modest, persistent declines in LVEF at 3 years. Changes in volumes, strain, and VA coupling were consistently associated with concurrent and subsequent LVEF declines and recovery across therapies. © 2017 by the American College of Cardiology Foundation and the American Heart Association, Inc.

Revere K.E.,The Childrens Hospital Of Philadelphia
Ophthalmic Plastic and Reconstructive Surgery | Year: 2017

PURPOSE:: The authors sought to compare the clinical outcomes of simultaneous versus sequential ptosis and strabismus surgery in children. METHODS:: Retrospective, single-center cohort study of children requiring both ptosis and strabismus surgery on the same eye. Simultaneous surgeries were performed during a single anesthetic event; sequential surgeries were performed at least 7 weeks apart. Outcomes were ptosis surgery success (margin reflex distance 1 ≥ 2 mm, good eyelid contour, and good eyelid crease); strabismus surgery success (ocular alignment within 10 prism diopters of orthophoria and/or improved head position); surgical complications; and reoperations. RESULTS:: Fifty-six children were studied, 38 had simultaneous surgery and 18 sequential. Strabismus surgery was performed first in 38/38 simultaneous and 6/18 sequential cases. Mean age at first surgery was 64 months, with mean follow up 27 months. A total of 75% of children had congenital ptosis; 64% had comitant strabismus. A majority of ptosis surgeries were frontalis sling (59%) or Fasanella-Servat (30%) procedures. There were no significant differences between simultaneous and sequential groups with regards to surgical success rates, complications, or reoperations (all p > 0.28). CONCLUSIONS:: In the first comparative study of simultaneous versus sequential ptosis and strabismus surgery, no advantage for sequential surgery was seen. Despite a theoretical risk of postoperative eyelid malposition or complications when surgeries were performed in a combined manner, the rate of such outcomes was not increased with simultaneous surgeries. Performing ptosis and strabismus surgery together appears to be clinically effective and safe, and reduces anesthesia exposure during childhood. © 2017 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Striano B.,The Childrens Hospital Of Philadelphia
Journal of Pediatric Orthopaedics | Year: 2017

BACKGROUND:: Although ultrasound (US) is frequently used in diagnosis and management of infantile developmental dysplasia of the hip, precise ultrasonographic parameters of what constitutes a dislocation, subluxation etc remain poorly defined. The purpose of this study was (1) to describe the ultrasonographic characteristics of a large cohort of clinically dislocated but reducible hips and (2) to begin to develop ultrasonographic definitions for what constitutes a hip dislocation. METHODS:: A retrospective review of prospectively collected data from an international multicenter study group on developmental dysplasia of the hip was conducted on all patients under 6 months of age with hip(s) that were dislocated at rest but reducible based on initial physical examination (ie, Ortolani positive). Femoral head coverage (FHC), alpha angle (α), and beta angle (β) were measured on pretreatment US by the individual treating surgeon, and were recorded directly into the database. RESULTS:: Based on 325 Ortolani positive hips, the median FHC on presentation was 10% with an interquartile range of 0% to 23%. A total of 126 of the 327 hips (39%) demonstrated 0% FHC. The 90th percentile was found to be at 33% FHC. Of 264 hips with sufficient α data, the median α was 43 degrees with an interquartile range from 37 to 49 degrees. The 90th percentile for α was at 54 degrees. A total of 164 hips had documented β with a median of 66 degrees and an interquartile range of 57 to 79 degrees; the 90th percentile was at 94 degrees. CONCLUSIONS:: Analysis of a large cohort of patients with dislocated but reducible hips reveals a median percent FHC of 10%, a median α of 43 degrees, and a median β of 66 degrees on initial US. Using a threshold at the 90th percentile, a sensible ultrasonographic definition of a dislocated hip seems to be FHC≤33%, implying that FHC between 34% and 50% may be reasonably termed a subluxation. Although these findings are consistent with previous, smaller reports, further prospective research is necessary to validate these thresholds. LEVEL OF EVIDENCE:: Level IV—diagnostic study.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Pacifici M.,The Childrens Hospital Of Philadelphia
Current Osteoporosis Reports | Year: 2017

Purpose of Review: Hereditary multiple exostoses (HME) is a complex musculoskeletal pediatric disorder characterized by osteochondromas that form next to the growth plates of many skeletal elements, including long bones, ribs, and vertebrae. Due to its intricacies and unresolved issues, HME continues to pose major challenges to both clinicians and biomedical researchers. The purpose of this review is to describe and analyze recent advances in this field and point to possible targets and strategies for future biologically based therapeutic intervention. Recent Findings: Most HME cases are linked to loss-of-function mutations in EXT1 or EXT2 that encode glycosyltransferases responsible for heparan sulfate (HS) synthesis, leading to HS deficiency. Recent genomic inquiries have extended those findings but have yet to provide a definitive genotype-phenotype correlation. Clinical studies emphasize that in addition to the well-known skeletal problems caused by osteochondromas, HME patients can experience, and suffer from, other symptoms and health complications such as chronic pain and nerve impingement. Laboratory work has produced novel insights into alterations in cellular and molecular mechanisms instigated by HS deficiency and subtending onset and growth of osteochondroma and how such changes could be targeted toward therapeutic ends. Summary: HME is a rare and orphan disease and, as such, is being studied only by a handful of clinical and basic investigators. Despite this limitation, significant advances have been made in the last few years, and the future bodes well for deciphering more thoroughly its pathogenesis and, in turn, identifying the most effective treatment for osteochondroma prevention. © 2017 Springer Science+Business Media New York

Elias M.D.,The Childrens Hospital Of Philadelphia
Pediatric Critical Care Medicine | Year: 2017

OBJECTIVE:: Extracorporeal membrane oxygenation is an important form of short-term mechanical support in children with cardiac disease, but information on long-term outcomes and quality of life is limited. The primary objective of this study was to determine the long-term outcomes of children previously supported by extracorporeal membrane oxygenation for cardiac etiologies. DESIGN:: A retrospective analysis was performed on patients with cardiac disease managed with extracorporeal membrane oxygenation between January 1, 1995, and December 31, 2012, at the Children’s Hospital of Philadelphia. Survivors completed patient- and parent-reported verbal and written surveys, and univariate analyses assessed risk factors for long-term outcomes. SETTING:: Tertiary-care children’s hospital. PATIENTS:: Patients with cardiac disease managed with extracorporeal membrane oxygenation. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: Over 18 years, 396 patients were managed with extracorporeal membrane oxygenation with 43% survival to discharge. The median age at cannulation was 78 days. The majority had congenital heart disease (86%), surgery prior to extracorporeal membrane oxygenation (71%), and cardiopulmonary arrest as the primary extracorporeal membrane oxygenation indication (53%). With 6-year median follow-up, 66% are known to be deceased, including 38 deaths after hospital discharge. Among survivors at discharge, 65 (38%) completed the phone survey, and 33 (19%) completed the written survey. Negative clinical outcomes, defined as having at least significant physical limitations or “fair” or “poor” health, were present in 18% of patients. No patient- or extracorporeal membrane oxygenation–related variables were associated with negative outcomes in univariate analyses. There were significantly lower self-reported and parent-reported written Pediatric Quality of Life Inventory quality of life scores in children compared with healthy individual normative data but no differences in adolescents. CONCLUSIONS:: In this series of pediatric cardiac patients supported by extracorporeal membrane oxygenation, mortality was 66% with 6-year median follow-up. The majority reported positive outcomes with respect to health and physical limitations, but children reported lower quality of life compared with healthy individuals. ©2017The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Law C.,The Childrens Hospital Of Philadelphia | Raffini L.,University of Pennsylvania
Pediatric Drugs | Year: 2015

Increasing thrombotic complications in children with complex medication conditions have led to more widespread use of anticoagulants [Raffini et al. in Pediatrics 124(4):1001–8, 2009]. While current guidelines for the management of antithrombotic therapy in neonates and children exist, they are based on low- and very low-quality evidence [Monagle et al. in Chest 141(2 Suppl):e737–801S, 2012]. Despite numerous differences, current anticoagulation practice is largely extrapolated from adult studies. This is sub-optimal, particularly in neonates who have a rapidly evolving hemostatic system. The majority of pediatric patients have underlying medical conditions that may significantly influence drug choice and bleeding risk. This article reviews the use of anticoagulants in children with thrombosis, focusing on practical aspects such as dosing, monitoring, and complications. Low molecular weight heparin has become the preferred anticoagulant in children, although unfractionated heparin and warfarin remain frequently used. Other anticoagulants, including fondaparinux, direct thrombin inhibitors, and the newer target-specific oral anticoagulants are also discussed. Given the many unique challenges surrounding the use of anticoagulants in children, pediatric hospitals should have written practice guidelines as well as experienced providers to care for children with thrombosis. This is an evolving field, and further studies of the use of anticoagulants in neonates and children are greatly needed to help optimize care. © 2015, Springer International Publishing Switzerland.

Refakis C.A.,The Childrens Hospital Of Philadelphia
Journal of Pediatric Orthopaedics | Year: 2016

BACKGROUND:: Although many studies have separately investigated the treatment of developmental dysplasia of the hip and spastic hip disease, little data exist regarding the treatment of infants with dislocated hips and underlying spasticity. The purpose of this study was to review our results after the surgical treatment of these infants. METHODS:: We retrospectively reviewed all children below 3 years of age who underwent hip reconstruction for dislocated hips in the setting of cerebral palsy or other spastic/high-tone neuromuscular disease. Medical records were reviewed for clinical data including treatment course, complications, and need for further surgery. Preoperative and postoperative radiographs were used to determine International Hip Dysplasia Institute (IHDI) grade of dislocation, acetabular index, migration percentage, and presence of avascular necrosis according to the Salter criteria. RESULTS:: Eleven patients with 15 hips met our inclusion criteria with a mean age of 20±8 (range, 6 to 34) months. Preoperatively, 12 of 15 hips (80%) were IHDI grade 4 and 3 of 15 (20%) were IHDI grade 3. Mean acetabular index was 29±8 (range, 19 to 46) degrees. Patients underwent open reduction (15 hips), adductor tenotomy (14 hips), femoral osteotomy (10 hips), and pelvic osteotomy (12 hips). At a mean follow-up of 40±16 (range, 13 to 71) months, 13 of 15 hips were IHDI grade 1 (86.7%), 1 was IHDI grade 2 (6.7%), and 1 hip was IHDI grade 3 (6.7%). The mean postoperative migration index was 7%±24% (range, −30% to 46%); the mean acetabular index was 22±8 (range, 9 to 38) degrees. No patients developed radiographically significant osteonecrosis. Complications included 2 femur fractures (13.3%) and 1 symptomatic implant that required early removal. One patient underwent further reconstructive hip surgery. CONCLUSIONS:: In this series of infants with hip dislocations and underlying spasticity, open reduction±pelvic osteotomy and/or femoral osteotomy has a nearly 90% success rate in achieving and maintaining adequate hip reduction at intermediate-term follow-up. In the unique population of infants with dislocated hips and underlying spasticity, comprehensive hip reconstruction is largely successful with an acceptable rate of complications. LEVEL OF EVIDENCE:: Level IV—retrospective. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Blevins E.,The Childrens Hospital Of Philadelphia
Journal of Pediatric Hematology/Oncology | Year: 2014

We report extensive thrombotic complications of inferior vena cava (IVC) filters that were placed for primary prophylaxis in 2 pediatric trauma patients with spinal cord injuries. Although thrombosis is a known common complication in adults with IVC filters, we were unable to find any reports in the literature of this complication in children. These cases highlight a significant problem with the use of prophylactic IVC filters that are not subsequently retrieved, particularly in young trauma patients with decades to live. The overall reported complications of IVC filters in the pediatric literature are also reviewed. © 2014 by Lippincott Williams & Wilkins.

Phillips M.C.,The Childrens Hospital Of Philadelphia
Sub-Cellular Biochemistry | Year: 2010

High density lipoprotein (HDL) possesses important anti-atherogenic properties and this review addresses the molecular mechanisms underlying these functions. The structures and cholesterol transport abilities of HDL particles are determined by the properties of their exchangeable apolipoprotein (apo) components. ApoA-I and apoE, which are the best characterized in structural terms, contain a series of amphipathic a-helical repeats. The helices located in the amino-terminal two-thirds of the molecule adopt a helix bundle structure while the carboxy-terminal segment forms a separately folded, relatively disorganized, domain. The latter domain initiates lipid binding and this interaction induces changes in conformation; the a-helix content increases and the amino-terminal helix bundle can open subsequently. These conformational changes alter the abilities of apoA-I and apoE to function as ligands for their receptors. The apoA-I and apoE molecules possess detergent-like properties and they can solubilize vesicular phospholipid to create discoidal HDL particles with hydrodynamic diameters of ~10 nm. In the case of apoA-I, such a particle is stabilized by two protein molecules arranged in an anti-parallel, double-belt, conformation around the edge of the disc. The abilities of apoA-I and apoE to solubilize phospholipid and stabilize HDL particles enable these proteins to be partners with ABCA1 in mediating efflux of cellular phospholipid and cholesterol, and the biogenesis of HDL particles. ApoA-I-containing nascent HDL particles play a critical role in cholesterol transport in the circulation whereas apoE-containing HDL particles mediate cholesterol transport in the brain. The mechanisms by which HDL particles are remodeled by lipases and lipid transfer proteins, and interact with SR-BI to deliver cholesterol to cells, are reviewed. © Springer Science+Business Media B.V. 2010.

The optimal autologous stem cell rescue (HDC-SCR) regimen for children with high-risk neuroblastoma (HR-NBL) is not defined. Carboplatin/etoposide/melphalan (CEM) is the current US standard; however, European data suggest busulfan/melphalan (Bu/Mel) may have less toxicity. Published data regarding toxicities associated with CEM and Bu/Mel are limited. We conducted a single-institution retrospective cohort study of children with HR-NBL who received CEM or Bu/Mel preparative regimens. Toxicity data were analyzed using χ2 or Fisher’s exact, Wilcoxon two-sample or log-rank tests. Sinusoidal obstruction syndrome (SOS) was observed in 7/44 CEM (15.9%) and 5/21 (24%) Bu/Mel patients (P=0.50). Median time to SOS was longer following Bu/Mel than CEM (20 versus 9 days, P=0.02). Pulmonary hypertension (PHTN) was observed in ~20% of children after Bu/Mel and none after CEM (P=0.01). CEM patients had more nephrotoxicity (P=0.001), packed red blood cell (P=0.02) and platelet transfusions (P=0.008), and days on maximum pain support (P=0.0007). Time to engraftment, length of stay, documented infection rates and HDC-SCR-related mortality were similar. Nephrotoxicity and resource utilization associated with cytopenias and mucositis were greater after CEM. Pulmonary toxicities were more severe after Bu/Mel, and increased vigilance for PHTN may be warranted, particularly in children with hypoxemia out of proportion to respiratory distress.Bone Marrow Transplantation advance online publication, 9 May 2016; doi:10.1038/bmt.2016.84. © 2016 Macmillan Publishers Limited

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