Faculty Bibliography

RATIONALE AND OBJECTIVES: Abdominopelvic computed tomography (APCT) is often performed in patients with skeletal Ewing sarcoma family of tumors during initial staging and for subsequent clinical indications, such as metastasis surveillance; however, its clinical impact is unknown. The purpose of this study was to evaluate whether these computed tomographic examinations alter oncologic management and therefore patient outcomes. MATERIALS AND METHODS: One hundred eight consecutive patients with skeletal Ewing sarcoma family of tumors seen from 1985 to 2008 were retrospectively reviewed to identify imaging workup, pathology, primary site, evidence of metastatic disease, and patient outcomes. Data were analyzed using Wilcoxon's rank sum tests. RESULTS: Sixty-five of the 108 patients (60%) underwent 342 abdominopelvic computed tomographic examinations during a mean follow-up period of 8.9 years. During this time period, only one of the 65 patients (1.5%) who underwent APCT was discovered to have abdominal metastatic disease. There was no significant difference in the incidence of metastatic disease to the skeleton or chest between the groups without and with APCT (P = .10). There were 26 pelvic and lumbosacral primaries (24%) and 82 limb primaries (76%). Subgroup analysis performed on the 82 patients with limb primaries without (n = 36) and with (n = 46) APCT showed no significant differences in metastatic incidence to the skeleton or chest (P = .14). CONCLUSIONS: This study indicates that APCT, associated with increased radiation exposure and health expenditure, has a limited role in initial staging and follow-up in patients with skeletal Ewing sarcoma, particularly in patients with limb primaries

BACKGROUND: Chest CT after pediatric trauma is frequently performed but its clinical impact, particularly with respect to surgical intervention, has not been adequately evaluated. OBJECTIVE: To assess the impact of chest CT compared with chest radiography on pediatric trauma management. MATERIALS AND METHODS: Two hundred thirty-five consecutive pediatric trauma patients who had both chest CT and radiography were identified. Images were reviewed and findings were categorized and correlated with subsequent chest interventions, blinded to final outcome and management. RESULTS: Of the 235 children, 38.3% (90/235) had an abnormal chest radiograph and 63.8% (150/235) had an abnormal chest CT (P < 0.0001). Chest interventions followed in 4.7% (11/235); of these, the findings could be made 1 cm above the dome of the liver in 91% (10/11). Findings requiring chest intervention included pneumothorax (PTX) and vertebral fractures. PTX was found on 2.1% (5/235) of chest radiographs and 20.0% (47/235) of chest CTs (P < 0.0001); 1.7% (4/235) of the children received a chest tube for PTX, 0.85% (2/235) seen on chest CT only. Vertebral fractures were present in 3.8% of the children (9/235) and 66.7% (6/9) of those cases were treated with spinal fusion or brace. There were no instances of mediastinal vascular injury. CONCLUSION: Most intrathoracic findings requiring surgical management in our population were identified in the lower chest and would be included in routine abdominopelvic CT exams; this information needs to be taken into consideration in the diagnostic algorithm of pediatric trauma patients

BACKGROUND:Previous studies of children with homozygous sickle cell anemia (SCA) show impaired growth and maturation. The correlation of this suboptimal growth with metabolic and hematological factors during puberty is poorly understood. PROCEDURE/METHODS:We studied a group of pre-adolescent children with SCA (19 males, 14 females) and healthy controls (16 males, 15 females) matched for race, sex, body size, and pubertal development. Height, weight, body mass index (BMI), and body composition changes were longitudinally assessed over a 2-year period and compared between the groups and with Z scores based on US growth charts. These changes were correlated with hemoglobin (Hgb) concentration and with energy expenditure (EE) measured using indirect whole-room calorimetry. RESULTS:Children with SCA progressed through puberty slower than control children. While, after 2 years, pubertal males with SCA were shorter, their annual increases in weight were not different from controls. The mean fat free mass (FFM) increments were significantly less in males and females with SCA than in control children. In males with SCA, growth in height declined over time and was significantly slower than in matched controls (P < 0.05). CONCLUSION/CONCLUSIONS:Growth delays were present during puberty in children with SCA. Decreased growth velocity in children with SCA was independently associated with decreased Hgb concentration and increased total EE.

BACKGROUND:Autosomal dominant inheritance of germline mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene are a major risk factor for pulmonary arterial hypertension (PAH). While previous studies demonstrated a difference in severity between BMPR2 mutation carriers and noncarriers, it is likely disease severity is not equal among BMPR2 mutations. We hypothesized that patients with missense BMPR2 mutations have more severe disease than those with truncating mutations. METHODS:Testing for BMPR2 mutations was performed in 169 patients with PAH (125 with a family history of PAH and 44 with sporadic disease). Of the 106 patients with a detectable BMPR2 mutation, lymphocytes were available in 96 to functionally assess the nonsense-mediated decay pathway of RNA surveillance. Phenotypic characteristics were compared between BMPR2 mutation carriers and noncarriers, as well as between those carriers with a missense versus truncating mutation. RESULTS:While there was a statistically significant difference in age at diagnosis between carriers and noncarriers, subgroup analysis revealed this to be the case only for females. Among carriers, there was no difference in age at diagnosis, death, or survival according to exonic location of the BMPR2 mutation. However, patients with missense mutations had statistically significant younger ages at diagnosis and death, as well as shorter survival from diagnosis to death or lung transplantation than those with truncating mutations. Consistent with this data, the majority of missense mutations were penetrant prior to age 36 years, while the majority of truncating mutations were penetrant after age 36 years. CONCLUSION/CONCLUSIONS:In this cohort, BMPR2 mutation carriers have more severe PAH disease than noncarriers, but this is only the case for females. Among carriers, patients with missense mutations that escape nonsense-mediated decay have more severe disease than those with truncating mutations. These findings suggest that treatment and prevention strategies directed specifically at BMPR2 pathway defects may need to vary according to the type of mutation.

Testing Hardy-Weinberg equilibrium (HWE) in the control group is commonly used to detect genotyping errors in genetic association studies. We propose a likelihood ratio test for testing HWE in the study population using both case and control samples. This test incorporates underlying association models. Another feature is that, when we infer the disease-genotype association, we explicitly incorporate HWE or a possible departure from Hardy-Weinberg equilibrium (DHWE) into the model. Our unified framework enables us to infer the disease-genotype association when a detected DHWE needs to be part of the model after causes for the DHWE are explored. Real data sets are used to illustrate the application of the methodology and its implication in genetic association studies. Our analysis and interpretation touch on issues such as genotyping errors, population selection, population stratification, or the study sampling plan, that all could be the cause of DHWE.

PURPOSE: To determine whether lack of visualization of the appendix on otherwise normal abdominopelvic computed tomographic (CT) images can help exclude appendicitis in the pediatric population. MATERIALS AND METHODS: The study was institutional review board approved and HIPAA compliant. One thousand one hundred thirty-nine children suspected of having appendicitis were referred for CT examination between July 2002 and December 2006. Exclusion criteria included CT diagnosis of appendicitis or other cause of symptoms and lack of clinical follow-up. Consensus review was performed by two pediatric radiologists to determine normal examinations, leaving a final study group (nonvisualized appendix) of 156 patients (mean age, 9.6 years; boys, 7.2 years; girls, 10.2 years) and a control group (visualized appendix) of 421 patients (mean age, 11.0 years; boys, 9.8 years; girls, 11.2 years). In the control group, there were 168 subjects with a partially visualized (PV) appendix and 253 with a fully visualized (FV) appendix. Pericecal fat was graded according to published criteria. Diagnosis was confirmed at surgery or clinical follow-up. Negative predictive values were calculated with 95% confidence intervals (CIs). RESULTS: There were three false-negative findings (study group, two; control group, one [FV]). The negative predictive value of a normal CT examination in pediatric patients with a nonvisualized appendix was 98.7% (95% CI: 95.5%, 99.8%); that with a visualized appendix, 99.8% (95% CI: 98.7%, 99.99%); that with a PV appendix, 100% (95% CI: 97.8%, 100%); and that with a FV appendix, 99.6% (95% CI: 97.8%, 99.99%). CONCLUSION: Pediatric abdominopelvic CT images with nonvisualized appendix have a high negative predictive value, without significant difference from cases with a PV or even FV appendix. The false-negative rate was similar to those reported in two adult series

Biomarkers of inflammation, especially C-reactive protein (CRP), have been consistently shown to predict poor outcomes in chronic hemodialysis (CHD) patients. However, the determinants of CRP and the value of its monitoring in CHD patients have not been well defined. We conducted a retrospective cohort study to evaluate possible determinants of the inflammatory response in CHD patients with a focus on dialysis catheter utilization. Monthly CRP were measured in 128 prevalent CHD patients (mean age 56.6 years [range 19-90], 68% African Americans, 39% diabetics [DM]) over a mean follow-up of 12 months (range 2-26 months). There were a total of 2405 CRP measurements (median 5.7 mg/L; interquartile range [IQR] 2.4-16.6 mg/L). The presence of a dialysis catheter (p<0.002), cardiovascular disease (p=0.01), male gender (p=0.005), higher white blood cell count (p<0.0001), elevated phosphorus (p=0.03), and lower cholesterol (p=0.02) and albumin (p<0.0001) concentrations were independent predictors of elevated CRP in the multivariate analysis. Additionally, CRP levels were significantly associated with the presence of a catheter, when comparing the levels before and after catheter insertion (p=0.002) as well as before and after catheter removal (p=0.009). Our results indicate that the presence of a hemodialysis catheter is an independent determinant of an exaggerated inflammatory response in CHD patients representing a potentially modifiable risk factor.

PURPOSE/OBJECTIVE:We hypothesized that functional TGFbeta1 SNPs increase TGFbeta/BMP signaling imbalance in BMPR2 mutation heterozygotes to accelerate the age at diagnosis, increase the penetrance and SMAD2 expression in familial pulmonary arterial hypertension. METHODS:Single nucleotide polymorphism genotypes of BMPR2 mutation heterozygotes, age at diagnosis, and penetrance of familial pulmonary arterial hypertension were compared and SMAD2 expression was studied in lung sections. RESULTS:BMPR2 mutation heterozygotes with least active -509 or codon 10 TGFbeta1 SNPs had later mean age at diagnosis of familial pulmonary arterial hypertension (39.5 and 43.2 years) than those with more active genotypes (31.6 and 33.1 years, P = 0.03 and 0.02, respectively). Kaplan-Meier analysis also showed that those with the less active single nucleotide polymorphisms had later age at diagnosis. BMPR2 mutation heterozygotes with nonsense-mediated decay resistant BMPR2 mutations and the least, intermediate and most active -509 TGFbeta1 SNP genotypes had penetrances of 33, 72, and 80%, respectively (P = 0.003), whereas those with 0-1, 2, or 3-4 active single nucleotide polymorphism alleles had penetrances of 33, 72, and 75% (P = 0.005). The relative expression of TGFbeta1 dependent SMAD2 was increased in lung sections of those with familial pulmonary arterial hypertension compared with controls. CONCLUSIONS:The TGFbeta1 SNPs studied modulate age at diagnosis and penetrance of familial pulmonary arterial hypertension in BMPR2 mutation heterozygotes, likely by affecting TGFbeta/BMP signaling imbalance. This modulation is an example of Synergistic Heterozygosity.