Purpose To assess the effect of intravenous contrast media on renal function in neonates. Materials and Methods Institutional review board approval was obtained with waiver of consent. Electronic health records from January 2011 to April 2013 were reviewed retrospectively. Measures of renal function were obtained in inpatient neonates who underwent magnetic resonance (MR) imaging or computed tomography (CT) and for whom serum creatinine (Cr) levels were obtained within 72 hours before imaging and at least one time after imaging (>1 day after administration of contrast material). A total of 140 neonates who received contrast material (59 who underwent CT with iohexol or iodixanol and 81 who underwent MR imaging with gadopentetate dimeglumine) were identified. These neonates were frequency matched according to sex, gestational and postnatal age, and preimaging serum Cr levels with neonates who underwent unenhanced MR imaging or CT. Cr levels and glomerular filtration rates (GFRs) were grouped according to when they were obtained (before imaging, 1-2 days after imaging, 3-5 days after imaging, 6-9 days after imaging, 10-45 days after imaging, and more than 45 days after imaging). Serum Cr levels and GFRs for each time period were compared between groups by using hierarchic regressions or χ2 or Fisher exact tests and with repeated-measures analysis of variance to compare groups on the rate of change in serum Cr levels and GFRs from before to after imaging. Results Cr levels decreased and GFRs increased in both groups from before to after imaging (CT group, P ≤ .01; MR imaging group, P ≤ .01). The neonates who underwent contrast material-enhanced imaging and the neonates who underwent unenhanced imaging showed similar serum Cr levels at all examined time periods. Groups also did not differ in the proportion of neonates with serum Cr levels higher than the reference range (>0.4 mg/dL) at any time point (iodine- [P > .12] or gadolinium-based [P > .13] contrast material). Similar findings were observed for GFRs. None of the neonates developed nephrogenic systemic fibrosis. Conclusion In the absence of known renal failure, neonates receiving standard inpatient care do not appear to be at increased risk for developing renal toxicity due to administration of intravenous iodine- and gadolinium-based contrast material. © RSNA, 2017.

Purpose: Human epigenetic studies reveal different cellular DNA methylation profiles in healthy and OA patients, suggesting that DNA methyltransferase (Dnmt) may play a role in regulating cartilage homeostasis. There are three Dnmts: Dnmt1 is ubiquitous and is involved in whole genome methylation homeostasis. In contrast, the de novo Dnmt3a and 3b have tissue specific expression patterns and can create unique methylation signatures. The goal of this study was to determine the role of Dnmt3b in cartilage health and disease. Methods: IHC was performed to check Dnmt3a and 3b expression in murine and human articular cartilage. Promoter luciferase and ChIP assays were performed in ATDC5 cells. Dnmt3b loss-of-function (LOF) mice (Dnmt3bAgc1ER) were generated to analyze OA-like phenotype at 5 and 8 mo of age. Whole genome bisulfite sequencing (Methyl-seq) and RNA-seq were performed to elucidate the downstream target of Dnmt3b in chondrocytes. HPLC-MS and oxygen consumption rate (OCR) were used to validate changes in TCA metabolites and mitochondria function. Dnmt3b gain-of-function (GOF) mice (Col2a1Cre; Rosa-rtTAf/+; Dnmt3b-tg) were generated to study meniscal ligament injury (MLI) induced OA. Results: Reduced Dnmt3b expression is associated with OA phenotype: IHC showed expression of Dnmt3b in normal murine and human articular cartilage. Dnmt3b expression decreased in murine cartilage with aging and following MLI-induced OA. An IHC array of 14 OA cartilage and 11 healthy cartilage similarly showed reduced DNMT3B expression in OA patients. Consistently, DNMT3B mRNA expression was significantly lower in OA cartilage and treatment of human chondrocytes with IL1β resulted in decreased DNMT3B mRNA and protein expression. Luciferase assays showed reduced Dnmt3b promoter activity following IL1β treatment of ATDC5 cells; this affect was attenuated following mutation of the NFκB binding site. ChIP assays showed that NFκB could interact with the predicted binding site. Dnmt3b LOF in vivo leads to a progressive OA-like pathology: Compared to controls, 5 mo Dnmt3b LOF mice showed OA features including fibrillation and loss of proteoglycan in cartilage tissue. The number of apoptotic cells was significantly increase in 5 mo Dnmt3b LOF cartilage. At 8 mo, histology showed osteophyte formation, loss of proteoglycan staining, and meniscus mineralization. OARSI scoring showed higher scores for both 5 and 8 mo Dnmt3b LOF mice. μCT analysis showed the presence of osteophytes and an increase in subchondral bone thickness in 8 mo Dnmt3b LOF mice. Metabolic pathways are altered in Dnmt3b LOF chondrocytes: Changes in gene expression and methylation profiles were investigated by integrative analysis of RNA-Seq and Methyl-Seq data. Analysis revealed 44 genes with altered expression and methylation profiles in LOF cells. Gene ontology analysis revealed an enrichment in several pathways, including the TGFβ pathway and cellular metabolism. We indeed found higher mitochondrial respiration correlated to an increase in catabolic genes in Dnmt3b LOF cells. HPLC-MS further validated that TCA metabolites, including succinate, fumarate and NADH, were increased in Dnmt3b LOF cells. Increased mitochondrial respiration induces chondrocyte hypertrophy: To determine if there is a correlation between mitochondrial respiration and chondrocyte hypertrophy, we treated WT chondrocytes with succinate and found an increase in hypertrophic chondrocyte markers, Runx2 and Mmp13. We then treated WT chondrocytes with antimycin A and rotenone following with BMP2 treatment to inhibit mitochondrial respiration. We found that addition of the inhibitors attenuated the effect of BMP2 on chondrocyte differentiation as shown by a decrease in mitochondrial OCR and decreases in hypertrophic marker expression. Dnmt3b GOF in vivo attenuates OA progression: MLI surgeries were performed on 10 wk male control and Dnmt3b GOF mice. Dnmt3b GOF mice displayed a protective effect against progression of injury-induced OA at 8 and 12 wks post MLI surgery. The apparent loss of cartilage tissue induced by MLI was not observed in the Dnmt3b GOF mice. OARSI scoring showed lower scores in Dnmt3b GOF mice. To determine if mitochondrial metabolism was altered in Dnmt3b GOF chondrocytes, Dnmt3b GOF or control cells were treated with BMP2 and we found that mitochondrial OCR of GOF cells were lower than in control cells. Conclusions: This study shows that Dnmt3b plays a significant role in regulating postnatal articular cartilage homeostasis. Cellular pathways regulated by Dnmt3b in chondrocytes may provide novel targets for therapeutic approaches to treat OA.

BackgroundThe combination of topotecan and cyclophosphamide is active in relapsed Ewing sarcoma family of tumors (ESFT). The feasibility of adding these agents combined with vincristine (vincristine-topotecan-cyclophosphamide [VTc]) to standard five-drug chemotherapy with vincristine-doxorubicin-cyclophosphamide (VDC) and ifosfamide-etoposide (IE) administered in an interval-compressed (2-week instead of 3-week intervals) schedule was investigated.ProcedureNewly diagnosed patients with localized ESFT < 31 years, with good performance status and adequate organ function were eligible. Seventeen alternating cycles of chemotherapy with VTc, VDC, and IE were administered at 2-week intervals. Local control (LC) of the primary tumor occurred following six cycles. Primary endpoints were the ability to deliver chemotherapy in an interval-compressed schedule, and the rate of grade 3 or greater nonhematologic toxicity and grade 4 hematologic toxicity, which delayed chemotherapy by 2 weeks. Secondary endpoints were event-free survival (EFS) and overall survival (OS).ResultsThirty-five patients with a median age of 11 years were enrolled. The mean time to last dose of chemotherapy prior to LC was 12.6 1.4 weeks and 45.5% of patients received intended chemotherapy without any delay prior to LC. There were no toxic deaths or unexpected toxicities. Five-year EFS was 79.6% (95% confidence interval [CI]: 61.8-89.7%) and 5-year OS was 88% (95% CI: 71.4-95.3%).ConclusionsThe addition of VTc to standard therapy was tolerable with sufficient interval compression compared to historical standard 3-week cycles.

Purpose EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-α-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy. Patients and Methods At diagnosis, patients age ≤ 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ≥ two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, < 10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-α-2b (0.5 to 1.0 μg/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary). Results Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-α-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-α-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-α-2b and for stopping prematurely, respectively. Median IFN-α-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-α-2b and provided toxicity information reported grade ≥ 3 toxicity during IFN-α-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-α-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model. Conclusion At the preplanned analysis time, MAP plus IFN-α-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-α-2b or stopped prematurely. Long-term follow-up for events and survival continues.

This manuscript describes the experience from registration until randomisation for a cohort of 2260 patients with osteosarcoma who joined the EURAMOS-1 trial. This includes pre-operative chemotherapy and surgery. It sets out the practical issues in collaboration and in achieving randomisation.

BACKGROUND Patients with Ewing sarcoma require local primary tumor control with surgery, radiation, or both. The optimal choice of local control for overall and local disease control remains unclear. METHODS Patients with localized Ewing sarcoma of bone who were treated on 3 consecutive protocols with standard‐dose, 5‐drug chemotherapy every 3 weeks were included (n=465). Propensity scores were used to control for differences between local control groups by constructing multivariate models to assess the impact of local control type on clinical endpoints (event‐free survival [EFS], overall survival, local failure, and distant failure) independent of differences in their propensity to receive each local control type. RESULTS Patients who underwent surgery were younger ( P =.02) and had more appendicular tumors ( P <.001). Compared with surgery, radiation had higher unadjusted risks of any event (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.18‐2.44), death (HR, 1.84; 95% CI, 1.18‐2.85), and local failure (HR, 2.57; 95% CI, 1.37‐4.83). On multivariate analysis, compared with surgery, radiation had a higher risk of local failure (HR, 2.41; 95% CI, 1.24‐4.68), although there were no significant differences in EFS (HR, 1.42; 95% CI, 0.94‐2.14), overall survival (HR, 1.37; 95% CI, 0.83‐2.26), or distant failure (HR, 1.13; 95% CI, 0.70‐1.84) between local control groups. CONCLUSIONS In this large group of similarly treated patients, choice of the mode of local control was not related significantly to EFS, overall survival, or distant failure, although the risk of local failure was greater for radiation compared with surgery. These data support surgical resection when appropriate, whereas radiotherapy remains a reasonable alternative in selected patients. Cancer 2015;121:467–475. © 2014 American Cancer Society .

Aim: Patients with metastatic osteosarcoma (OS) have a poor outcome with conventional therapies. Zoledronic acid (ZA) is a third-generation bisphosphonate that reduces skeletal-related events in many adult cancers, and pre-clinical data suggest a possible benefit in OS. This study assessed the maximum tolerated dose (MTD) and the feasibility of ZA when combined with chemotherapy in patients with metastatic OS.Patients and Methods: Patients with a histological diagnosis of OS were eligible if they were <40 years of age, had initially metastatic disease and met organ function requirements. Treatment combined surgery and a conventional chemotherapy regimen. ZA was given concurrent with chemotherapy for a total of eight doses over 36 weeks. Three dose levels of ZA were tested: 1.2 mg/m(2) [max 2 mg], 2.3 mg/m(2) [max 4 mg] and 3.5 mg/m(2) [max 6 mg]. The MTD was determined during induction. Six patients were to be treated at each dose level, with an additional six patients treated with the MTD to help assess post-induction feasibility.Results: Twenty-four patients (median age 13.5 years [range, 7-22]; 16 females) were treated. Five patients experienced dose-limiting toxicities (DLTs) during induction, including three patients treated with 3.5 mg/m(2). DLTs included hypophosphatemia, hypokalemia, hyponatremia, mucositis, limb pain and limb oedema. There were no reports of excessive renal toxicity or osteonecrosis of the jaw. The MTD was defined as 2.3 mg/m(2) (max 4 mg).Conclusions: ZA can be safely combined with conventional chemotherapy with an MTD of 2.3 mg/m(2) (max 4 mg) for patients with metastatic osteosarcoma. (c) 2013 Elsevier Ltd. All rights reserved.

PURPOSE To validate a multicenter protocol that examines lower extremity skeletal muscles of children with Duchenne muscular dystrophy (DMD) by using magnetic resonance (MR) imaging and MR spectroscopy in terms of reproducibility of these measurements within and across centers. MATERIALS AND METHODS This HIPAA-compliant study was approved by the institutional review boards of all participating centers, and informed consent was obtained from each participant or a guardian. Standardized procedures with MR operator training and quality assurance assessments were implemented, and data were acquired at three centers by using different 3-T MR imaging instruments. Measures of maximal cross-sectional area (CSAmax), transverse relaxation time constant (T2), and lipid fraction were compared among centers in two-compartment coaxial phantoms and in two unaffected adult subjects who visited each center. Also, repeat MR measures were acquired twice on separate days in 30 boys with DMD (10 per center) and 10 unaffected boys. Coefficients of variation (CVs) were computed to examine the repeated-measure variabilities within and across centers. RESULTS CSAmax, T2 from MR imaging and MR spectroscopy, and lipid fraction were consistent across centers in the phantom (CV, <3%) and in the adult subjects who traveled to each site (CV, 2%-7%). High day-to-day reproducibility in MR measures was observed in boys with DMD (CSAmax, CV = 3.7% [25th percentile, 1.3%; 75th percentile, 5.1%]; contractile area, CV = 4.2% [25th percentile, 0.8%; 75th percentile, 4.9%]; MR imaging T2, CV = 3.1% [25th percentile, 1.2%; 75th percentile, 4.7%]; MR spectroscopy T2, CV = 3.9% [25th percentile, 1.5%; 75th percentile, 5.1%]; and lipid fraction, CV = 4.7% [25th percentile, 1.0%; 75th percentile, 5.3%]). CONCLUSION The MR protocol implemented in this multicenter study achieved highly reproducible measures of lower extremity muscles across centers and from day to day in ambulatory boys with DMD.

9537 Background: Patients (pts) with Ewing sarcoma (EWS) require local control, either with surgery alone (S), radiation alone (R), or a combination of surgery + radiation (S+R). Optimal choice of local control for disease control remains unclear. Our primary aim was to determine the mode of local control associated with the highest event-free survival (EFS). Methods: Pts with localized EWS of bone treated on INT0091, INT0154, or AEWS0031 phase III trials were included if they had complete local control data, did not have cranial tumors, received local control starting 2-6 months after enrollment, and were randomized to receive standard dose 5-drug chemotherapy every 3 weeks. We used propensity scores to control for differences in age, tumor site, and year of diagnosis between local control groups. We constructed Cox models controlling for local control propensity scores to assess the impact of local control type on EFS and overall survival (OS) from the start of local control. Results: 465 pts were included. Pts selected for S were treated more recently (p < 0.001), more likely to have appendicular tumors (p < 0.001), and younger (p = 0.02). Pts treated with R, compared to S, had higher unadjusted risk of any event (HR 1.70; 95% CI 1.18 - 2.44; p = 0.004) or death (HR 1.84; 95% CI 1.18 – 2.85; p = 0.006). Pts treated with S+R, compared to S, had higher unadjusted risk of death (HR 1.75; 95% CI 1.10 – 2.76; p = 0.02). After adjusting for propensity scores, there was a trend of higher risk of any event for pts treated with R (HR 1.42; 95% CI 0.94 – 2.14; p = 0.10) compared to S, though this was not statistically significant. No other differences in adjusted risk of event or death between local control groups were statistically significant. We confirmed these results with standard Cox models using age, tumor site, and year of diagnosis as covariates. Conclusions: In this large group of uniformly treated pts, investigator choice of local control approach was not significantly related to EFS. These data support current practice of surgical resection when feasible, while validating radiotherapy as a reasonable alternative in selected pts.

The appropriate imaging for pediatric patients (ages 0-5 years) being evaluated for limping depends on the clinical presentation, specifically, the presence of signs of infection, any localization of pain, and history of or suspected trauma. Common diagnoses causing limping in children are briefly reviewed, and recommended imaging techniques are discussed, including toddler's fracture, transient synovitis, septic arthritis, Legg-Calvé-Perthes disease, and osteomyelitis. The ACR Appropriateness Criteria(®) are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

This article reviews the roles of specific imaging modalities in the diagnosis and management of noncentral nervous system childhood cancer. Imaging modalities to be discussed include conventional radiography, ultrasound, computed tomography, magnetic resonance imaging, and nuclear medicine, including positron emission tomography. Emerging imaging techniques will also be discussed. Current literature will be referenced for more in-depth review.

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.

A regularly scheduled meeting or conference is a straightforward and effective activity to help build a culture of quality in your department. This gathering should bring together interested parties across the spectrum of radiology care delivery and include radiologists, technologists, nurses, clerical staff members, and administration. The diverse nature of the group will provide a holistic perspective to understanding system processes that invariably cross boundaries of responsibility. This forum can help fulfill radiologists' ABR Practice Quality Improvement Maintenance of Certification requirements [ 1 Strife J. Kun L.E. Becker G.J. Dunnick N.R. Bosma J. Hattery R.R. The American Board of Radiology perspective on maintenance of certification: part IV—practice quality improvement in diagnostic radiology. J Am Coll Radiol. 2007; 4: 300-304 Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar ] and residents' ACGME IV systems-based practice requirements [ 2 Mainiero M.B. Incorporating ACR Practice Guidelines, Technical Standards, and Appropriateness Criteria into resident education. J Am Coll Radiol. 2004; 1: 277-279 Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar ] and can assist in departmental preparations for a Joint Commission visit [ 3 Donnelly L. Performance-based assessment of radiology practitioners: promoting improvement in accordance with the 2007 Joint Commission standards. J Am Coll Radiol. 2007; 5: 699-703 Abstract Full Text Full Text PDF Scopus (31) Google Scholar ]. More important, a successful meeting can provide a valuable open channel of communication within a department and act as both an early warning system concerning systemic failures and an important bridge to maintaining healthy relations between the hospital staff and the physician practice. Another important purpose is to narrow the authority power distance and acknowledge the equal roles of the all department members in patient safety.

As radiology departments convert to digital imaging, the acquisition, reading,and management of scoliosis studies pose unique challenges. This case study assesses the actual impact on efficiency,file management, cost, and clinical acceptability after a conversion to see whether goals were accomplished. As digital imaging for scoliosis studies became the new standard of care in the Children's Hospital of Philadelphia radiology department, it renewed interest and attention to these disorders and facilitated improved patient care.

Purpose The Ewing sarcoma family of tumors (ESFT) is a group of malignant tumors of soft tissue and bone sharing a chromosomal translocation affecting the EWS locus. The Intergroup INT-0091 demonstrated the superiority of a regimen of vincristine, cyclophosphamide, doxorubicin (VDC), and dactinomycin alternating with ifosfamide and etoposide (IE) over VDC for patients with nonmetastatic ESFT of bone. The goal of this study was to determine whether a dose-intensified regimen of VDC alternating with IE would further improve the outcome for patients with nonmetastatic ESFT of bone or soft tissue. Methods Patients with previously untreated, nonmetastatic ESFT of bone or soft tissue were eligible. They were randomly assigned to receive standard doses of VDC/IE over 48 weeks or a dose-intensified regimen of VDC/IE over 30 weeks. Results Four hundred seventy-eight patients met eligibility requirements: 231 patients received the standard regimen; 247 patients received the intensified regimen. The 5-year event-free survival (EFS) and overall survival rates for all eligible patients were 71.1% (95% CI, 67.7% to 75.0%) and 78.6% (95% CI, 74.6% to 82.1%), respectively. There was no significant difference (P = .57) in EFS between patients treated with the standard (5-year EFS, 72.1%; 95% CI, 65.8% to 77.5%) or intensified regimen (5-year EFS, 70.1%; 63.9% to 75%). Patients with soft tissue tumors accounted for 20% of the study population; there was no difference in outcome between patients with soft tissue and bone primary sites. Conclusion Dose escalation of alkylating agents as tested in this trial did not improve the outcome for patients with nonmetastatic ESFT of bone or soft tissue.

The Children's Oncology Group (COG) is a multi-institutional cooperative group dedicated to childhood cancer research that has helped to increase the survival of children with cancer through clinical trials. These clinical trials include a standardized regimen of imaging examinations performed prior to, during, and following therapy. This article presents imaging guidelines developed by a multidisciplinary group from the COG Bone Tumor Committee. These guidelines provide both required and recommended studies. Recommended examinations may become required in the future. These guidelines should be considered a work in progress that will evolve with advances in imaging and childhood cancer research.

MR imaging plays a major role in the assessment of pediatric musculoskeletal disease. Compared with 1.5 T MR imaging, 3 T magnets provide images with an increased signal-to-noise ratio, which is particularly helpful when assessing small body parts and structures in children. This article discusses the advantages and challenges associated with musculoskeletal MR imaging at 3 T, basic scanning protocols, image optimization techniques, and specific clinical applications in a pediatric population.