Showing papers by "Primary Children's Hospital published in 2011"

Sequential vs Concurrent Chemoradiation for Stage III Non–Small Cell Lung Cancer: Randomized Phase III Trial RTOG 9410

Abstract: Background The combination of chemotherapy with thoracic radiotherapy (TRT) compared with TRT alone has been shown to confer a survival advantage for good performance status patients with stage III non–small cell lung cancer. However, it is not known whether sequential or concurrent delivery of these therapies is the optimal combination strategy.

Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas

Abstract: Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.

FilmArray, an automated nested multiplex PCR system for multi-pathogen detection: development and application to respiratory tract infection.

Abstract: The ideal clinical diagnostic system should deliver rapid, sensitive, specific and reproducible results while minimizing the requirements for specialized laboratory facilities and skilled technicians. We describe an integrated diagnostic platform, the “FilmArray”, which fully automates the detection and identification of multiple organisms from a single sample in about one hour. An unprocessed biologic/clinical sample is subjected to nucleic acid purification, reverse transcription, a high-order nested multiplex polymerase chain reaction and amplicon melt curve analysis. Biochemical reactions are enclosed in a disposable pouch, minimizing the PCR contamination risk. FilmArray has the potential to detect greater than 100 different nucleic acid targets at one time. These features make the system well-suited for molecular detection of infectious agents. Validation of the FilmArray technology was achieved through development of a panel of assays capable of identifying 21 common viral and bacterial respiratory pathogens. Initial testing of the system using both cultured organisms and clinical nasal aspirates obtained from children demonstrated an analytical and clinical sensitivity and specificity comparable to existing diagnostic platforms. We demonstrate that automated identification of pathogens from their corresponding target amplicon(s) can be accomplished by analysis of the DNA melting curve of the amplicon.

Report from a consensus conference on antibody-mediated rejection in heart transplantation

Abstract: Background The problem of AMR remains unsolved because standardized schemes for diagnosis and treatment remains contentious. Therefore, a consensus conference was organized to discuss the current status of antibody-mediated rejection (AMR) in heart transplantation. Methods The conference included 83 participants (transplant cardiologists, surgeons, immunologists and pathologists) representing 67 heart transplant centers from North America, Europe, and Asia who all participated in smaller break-out sessions to discuss the various topics of AMR and attempt to achieve consensus. Results A tentative pathology diagnosis of AMR was established, however, the pathologist felt that further discussion was needed prior to a formal recommendation for AMR diagnosis. One of the most important outcomes of this conference was that a clinical definition for AMR (cardiac dysfunction and/or circulating donor-specific antibody) was no longer believed to be required due to recent publications demonstrating that asymptomatic (no cardiac dysfunction) biopsy-proven AMR is associated with subsequent greater mortality and greater development of cardiac allograft vasculopathy. It was also noted that donor-specific antibody is not always detected during AMR episodes as the antibody may be adhered to the donor heart. Finally, recommendations were made for the timing for specific staining of endomyocardial biopsy specimens and the frequency by which circulating antibodies should be assessed. Recommendations for management and future clinical trials were also provided. Conclusions The AMR Consensus Conference brought together clinicians, pathologists and immunologists to further the understanding of AMR. Progress was made toward a pathology AMR grading scale and consensus was accomplished regarding several clinical issues.

Targeting Axl and Mer kinases in cancer.

Abstract: Receptor tyrosine kinases (RTK) are cell-surface transmembrane receptors that contain regulated kinase activity within their cytoplasmic domain and play an important role in signal transduction in both normal and malignant cells. The mammalian TAM RTK family includes 3 closely related members: Tyro-3, Axl, and Mer. Overexpression or ectopic expression of the TAM receptors has been detected in a wide array of human cancers. Growth arrest-specific gene 6 has been identified as the major ligand for these TAM RTKs, and its binding to the receptors has been shown to promote proliferation and survival of cancer cells in vitro. Abnormal expression and activation of Axl or Mer can provide a survival advantage for certain cancer cells. Inhibition of Axl and Mer may enhance the sensitivity of cancer cells to cytotoxic agents and would potentially be a therapeutic strategy to target cancer cells. This review elucidates the role of Axl and Mer in normal cellular function and their role in oncogenesis. In addition, we review the potential to inhibit these RTKs for the development of therapeutic targets in treatment of cancer.

Extracorporeal membrane oxygenation for pediatric respiratory failure: Survival and predictors of mortality.

Abstract: Objective:The last multicentered analysis of extracorporeal membrane oxygenation in pediatric acute respiratory failure was completed in 1993. We reviewed recent international data to evaluate survival and predictors of mortality.Design:Retrospective case series review.Setting:The Extracorporeal Lif

A standardized protocol to reduce cerebrospinal fluid shunt infection: The Hydrocephalus Clinical Research Network Quality Improvement Initiative

Abstract: Object Quality improvement techniques are being implemented in many areas of medicine. In an effort to reduce the ventriculoperitoneal shunt infection rate, a standardized protocol was developed and implemented at 4 centers of the Hydrocephalus Clinical Research Network (HCRN). Methods The protocol was developed sequentially by HCRN members using the current literature and prior institutional experience until consensus was obtained. The protocol was prospectively applied at each HCRN center to all children undergoing a shunt insertion or revision procedure. Infections were defined on the basis of CSF, wound, or pseudocyst cultures; wound breakdown; abdominal pseudocyst; or positive blood cultures in the presence of a ventriculoatrial shunt. Procedures and infections were measured before and after protocol implementation. Results Twenty-one surgeons at 4 centers performed 1571 procedures between June 1, 2007, and February 28, 2009. The minimum follow-up was 6 months. The Network infection rate decreased fr...

An emergency department septic shock protocol and care guideline for children initiated at triage

Abstract: BACKGROUND: Unrecognized and undertreated septic shock increases morbidity and mortality. Septic shock in children is defined as sepsis and cardiovascular organ dysfunction, not necessarily with hypotension. OBJECTIVE: Cases of unrecognized and undertreated septic shock in our emergency department (ED) were reviewed with a focus on (1) increased recognition at triage and (2) more aggressive treatment once recognized. We hypothesized that septic shock protocol and care guideline would expedite identification of septic shock, increase compliance with recommended therapy, and improve outcomes. METHODS: We developed an ED septic shock protocol and care guideline to improve recognition beginning at triage and evaluated all eligible ED patients from January 2005 to December 2009. RESULTS: We identified 345 pediatric ED patients (49% male, median age: 5.6 years), and 297 (86.1%) met septic shock criteria at triage. One hundred ninety-six (56.8%) had ≥1 chronic complex condition. Hypotension was present in 34% (n = 120); the most common findings were tachycardia (n = 251 [73%]) and skin-color changes (n = 269 [78%]). The median hospital length of stay declined over the study period (median: 181–140 hours; P CONCLUSIONS: Implementation of an ED septic shock protocol and care guideline improved compliance in delivery of rapid, aggressive fluid resuscitation and early antibiotic and oxygen administration and was associated with decreased length of stay.

Impact of early and concurrent stunting on cognition.

Abstract: Undernutrition is associated with poor cognitive development, late entry into school, decreased years of schooling, reduced productivity and smaller adult stature. We use longitudinal data from 1674 Peruvian children participating in the Young Lives study to assess the relative impact of early stunting (stunted at 6-18 months of age) and concurrent stunting (stunted at 4.5-6 years of age) on cognitive ability. Anthropometric data were longitudinally collected for children at 6-18 months of age and 4.5-6 years of age at which time verbal and quantitative ability were also assessed. We estimate that an increase in concurrent height-for-age z-scores (HAZ) by one standard deviation was associated with an increase in a child's score on the Peabody Picture Vocabulary Test (PPVT) by 2.35 points [confidence interval (CI): 1.55-3.15] and a 0.16 point increase on the cognitive development assessment (CDA) (CI: 0.05-0.27). Furthermore, we report that the estimate for concurrent HAZ and PPVT is significantly higher than the estimate for early stunting and PPVT. We found no significant difference between early and concurrent estimates for HAZ and CDA. Children from older mothers, children whose mothers had higher education levels, children living in urban areas, children who attended pre-school, children with fewer siblings and children from wealthier backgrounds scored higher on both assessments. Cognitive skills of children entering school were associated with early stunting but the strongest association was found with concurrent stunting suggesting that interventions preventing linear growth faltering should not only focus on the under 2s but include children up to 5 years of age.

Complete Surgical Resection Is Curative for Children With Hepatoblastoma With Pure Fetal Histology: A Report From the Children's Oncology Group

Abstract: Purpose Children with pure fetal histology (PFH) hepatoblastoma treated with complete surgical resection and minimal adjuvant therapy have been shown to have excellent outcomes when compared with other patients with hepatoblastoma. We prospectively studied the safety and efficacy of reducing therapy in all children with stage I PFH enrolled onto two consecutive studies. Patients and Methods From August 1989 to December 1992, 9 children with stage I PFH were treated on the Intergroup Hepatoblastoma study INT-0098 and were nonrandomly assigned to receive chemotherapy after surgical resection with single-agent bolus doxorubicin for 3 consecutive days. From March 1999 to November 2006, 16 children with stage I PFH enrolled onto Children's Oncology Group Study P9645 were treated with observation after resection. Central confirmation of the histologic diagnosis by a study group pathologist was mandated. The extent of liver disease was assigned retrospectively according to the pretreatment extent of disease (PRE...

Molecular Analysis Improves Pathogen Identification and Epidemiologic Study of Pediatric Parapneumonic Empyema

Abstract: Parapneumonic empyema (PPE) is a serious complication of bacterial pneumonia that is becoming more common.1 Recently published reports implicate Streptococcus pneumoniae serotypes not contained within the 7-valent pneumococcal conjugate vaccine (PCV-7; Wyeth, Madison, NJ), and Staphylococcus aureus, particularly MRSA as important pathogens. 2, 3 For the most part these data rely on culture-based pathogen identification. Unfortunately, in most children with PPE the bacterial etiology is unknown.3–9 The low rate of pathogen detection complicates clinical care and selection of appropriate antibiotics. There are several factors that contribute to difficulties in isolating bacterial pathogens in patients with PPE. The most significant factor is likely the pre-treatment of children with antibiotics prior to obtaining blood or pleural fluid cultures. In addition, recovery of S. pneumoniae in culture is inherently difficult, due both to its sensitivity to transport conditions and its propensity for autolysis.10 The combination of these factors leads to a high rate of culture-negative disease (up to 60% of cases).3, 4 Thus the reliance on culture-based methodologies may be an impediment to accurately understanding of the epidemiology of PPE. Our institution has had an increasing rate of pediatric PPE for more than a decade. The incidence increased more than 10-fold between 1993 and 2007, from 1/100,000 to 12.5/100,000. 4,11 Previous studies have defined the epidemiology of culture-positive PPE in Utah children,11, 12 however the etiology of culture-negative disease has remained elusive. Recent studies from other centers have shown promising results using culture-independent techniques to determine the etiologic diagnosis of PPE.5, 7, 13–15 We have developed PCR-based assays that can detect and identify the major bacteria thought to be responsible for PPE. Additionally, our collaborators in Spain have developed PCR-based serotypying assays for pneumococci.16 Using these molecular assays we sought to 1) evaluate pleural fluid specimens from children with PPE to better define the etiology and epidemiology of disease 2) compare PCR-based detection of pathogens to culture-based detection and 3) compare data from patients culture-positive for a bacterial pathogen in blood or pleural fluid to data from patients in whom cultures were negative in an effort to identify whether there were differences in pathogens, pneumococcal serotypes, clinical presentation and/or outcomes between culture-positive and culture negative PPE.

ACR Appropriateness Criteria(®) on suspected physical abuse-child.

Abstract: The appropriate imaging for pediatric patients being evaluated for suspected physical abuse depends on the age of the child, the presence of neurologic signs and symptoms, evidence of thoracic or abdominopelvic injuries, and whether the injuries are discrepant with the clinical history. The clinical presentations reviewed consider these factors and provide evidence-based consensus recommendations by the ACR Appropriateness Criteria ® Expert Panel on Pediatric Imaging.

The Effect of Observation on Cranial Computed Tomography Utilization for Children After Blunt Head Trauma

Abstract: OBJECTIVE: Children with minor blunt head trauma often are observed in the emergency department before a decision is made regarding computed tomography use. We studied the impact of this clinical strategy on computed tomography use and outcomes. METHODS: We performed a subanalysis of a prospective multicenter observational study of children with minor blunt head trauma. Clinicians completed case report forms indicating whether the child was observed before making a decision regarding computed tomography. We defined clinically important traumatic brain injury as an intracranial injury resulting in death, neurosurgical intervention, intubation for longer than 24 hours, or hospital admission for 2 nights or longer. To compare computed tomography rates between children observed and those not observed before a decision was made regarding computed tomography use, we used a generalized estimating equation model to control for hospital clustering and patient characteristics. RESULTS: Of 42 412 children enrolled in the study, clinicians noted if the patient was observed before making a decision on computed tomography in 40 113 (95%). Of these, 5433 (14%) children were observed. The computed tomography use rate was lower in those observed than in those not observed (31.1% vs 35.0%; difference: −3.9% [95% confidence interval: −5.3 to −2.6]), but the rate of clinically important traumatic brain injury was similar (0.75% vs 0.87%; difference: −0.1% [95% confidence interval: −0.4 to 0.1]). After adjustment for hospital and patient characteristics, the difference in the computed tomography use rate remained significant (adjusted odds ratio for obtaining a computed tomography in the observed group: 0.53 [95% confidence interval: 0.43–0.66]). CONCLUSIONS: Clinical observation was associated with reduced computed tomography use among children with minor blunt head trauma and may be an effective strategy to reduce computed tomography use.

SMA CARNI-VAL TRIAL PART II: A Prospective, Single-Armed Trial of L-Carnitine and Valproic Acid in Ambulatory Children with Spinal Muscular Atrophy

Abstract: Background Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and l-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2–8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children. Methods This study involved 33 genetically proven type 3 SMA subjects ages 3–17 years. Subjects underwent two baseline assessments over 4–6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores. Results Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful. Conclusions This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA. Trial Regsitration Clinicaltrials.gov NCT00227266

Use of the ETV Success Score to explain the variation in reported endoscopic third ventriculostomy success rates among published case series of childhood hydrocephalus.

Abstract: Object Published case series of endoscopic third ventriculostomy (ETV) for childhood hydrocephalus have reported widely varying success rates. The authors recently developed and internally validated the ETV Success Score (ETVSS); this is a simplified means of predicting the 6-month success rate of ETV for a child with hydrocephalus, based on age, etiology of hydrocephalus, and presence of a previous shunt. The authors hypothesized that the ETVSS would be able to predict with reasonable accuracy the actual ETV success rate reported among published case series. Methods A literature search was performed to identify published pediatric ETV papers that contained enough information with which to calculate an aggregate, mean predicted ETVSS for the cohort. This was then compared with the actual ETV success rate in the cohort. Data were extracted independently in triplicate, including by 2 individuals who were not involved with the development of the ETVSS. Results Fifteen papers reporting on 322 patients were in...

Left ventricular assist device unloading effects on myocardial structure and function: current status of the field and call for action.

Abstract: Purpose of reviewMyocardial remodeling driven by excess pressure and volume load is believed to be responsible for the vicious cycle of progressive myocardial dysfunction in chronic heart failure. Left ventricular assist devices (LVADs), by providing significant volume and pressure unloading, allow

Genome-Wide Significance and Replication of the Chromosome 12p11.22 Locus Near the PTHLH Gene for Peripartum Cardiomyopathy

Abstract: Background—Peripartum (PP) cardiomyopathy (CM) is a rare condition of unknown etiology that occurs in late pregnancy or early postpartum. Initial evidence suggests that genetic factors may influenc...

Renin-Angiotensin-Aldosterone Genotype Influences Ventricular Remodeling in Infants With Single Ventricle

Abstract: Background—We investigated the effect of polymorphisms in the renin-angiotensin-aldosterone system (RAAS) genes on ventricular remodeling, growth, renal function, and response to enalapril in infants with single ventricle. Methods and Results—Single ventricle infants enrolled in a randomized trial of enalapril were genotyped for polymorphisms in 5 genes: angiotensinogen, angiotensin-converting enzyme, angiotensin II type 1 receptor, aldosterone synthase, and chymase. Alleles associated with renin-angiotensin-aldosterone system upregulation were classified as risk alleles. Ventricular mass, volume, somatic growth, renal function using estimated glomerular filtration rate, and response to enalapril were compared between patients with ≥2 homozygous risk genotypes (high risk), and those with <2 homozygous risk genotypes (low risk) at 2 time points: before the superior cavopulmonary connection (pre-SCPC) and at age 14 months. Of 230 trial subjects, 154 were genotyped: Thirty-eight were high risk, and 116 were ...

Critical review of controversial issues in the management of advanced pediatric liver tumors

Abstract: Hepatocellular carcinoma (HCC) and hepatoblastoma (HB) are the most common primary tumors of liver in children. The management of patients with locally advanced, unresectable disease or those with extra-hepatic distant metastases provides substantial challenges to pediatric oncologists, hepatologists, and surgeons. Herein, we critically debate the two sides of three specific controversies: (1) the role of chemotherapy in the treatment of advanced pediatric HCC; (2) the indications for liver transplantation in children with HCC, specifically, the appropriateness of using adult Milan criteria; and (3) the role of liver trasplantation in children with unresectable HB that present with metastatic disease. Pediatr Blood Cancer 2011;56:1013-1018. © 2010 Wiley-Liss, Inc.

Rejection with hemodynamic compromise in the current era of pediatric heart transplantation: a multi-institutional study.

Abstract: Background Survival after pediatric heart transplant has improved over time, as has the incidence of overall rejection. We studied the effect of era on the occurrence and outcome of rejection with hemodynamic compromise (HC). Methods Data from 2227 patients who received allografts between 1993 and 2006 at 36 centers in the Pediatric Heart Transplant Study were analyzed to determine incidence, outcome, and risk factors for rejection with HC in early (1993–1999) and recent (2000–2006) eras. Rejection with HC was classified as severe (RSHC) when inotropes were used for circulatory support and mild (RMHC) when inotropes were not used. Results Of 1217 patients with any episode of rejection, 541 had rejection with HC. Freedom from RMHC improved at 1 year (81% vs 90%, p p p = 0.24). Survival after RSHC (63% at 1 year and 49% at 5 years) was worse than after RMHC (87% at 1 year and 72% at 5 years, p p p = 0.01), and non-A blood type (HR, 1.51;, 95% CI, 1.11–2.04,; p = 0.01), but the only risk factor for RMHC was earlier era of transplant (HR, 1.94; 95% CI, 1.56–2.41; p Conclusions The incidence of RMHC has declined over time but the same era effect has not occurred with RSHC. Close follow-up after RSHC is crucial because mortality is so high.

Correlation of age-specific phenylalanine levels with intellectual outcome in patients with phenylketonuria

Abstract: Patients with treated phenylketonuria (PKU) can have subtle deficits in intellect, academic skills, and executive functioning. This study evaluates the relationship between intellectual outcome and concentration/variation in blood phenylalanine (Phe) during specific developmental periods (0–6 years, 7–12 years, >12 years) in our patients with PKU. Verbal comprehension, perceptual reasoning, and processing speed were used as measures of intelligence. Data were collected from 55 patients receiving treatment at the University of Utah Metabolic Clinic. Yearly median Phe levels increased and mean number of blood Phe samples decreased as patients aged. Yearly median blood Phe from 0–6 and 7–12 years were inversely associated with perceptual reasoning abilities using linear regression. Additionally, increased blood Phe concentration negatively impacted specific areas of verbal comprehension abilities for those 0–6 years of age (p = 0.001). Variation of Phe levels around the mean (assessed as standard deviation) in each patient was associated with diagnostic (highest pretreatment) Phe levels and yearly median Phe levels (p < 0.001 for both), but did not significantly impact intelligence in our group of patients. Frequent blood Phe monitoring from 7–12 years significantly reduced the probability of yearly median Phe exceeding 360 μM (p = 0.005). Our data show that compliance with treatment in patients with PKU affects both the concentration and variation of blood Phe levels, and may have a greater impact on verbal comprehension and perceptual reasoning skills during the first 12 years of life when compared the influence beyond 12 years.