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The detection of tumor-specific nucleic acids from blood increasingly is being used as a method of liquid biopsy and minimal residual disease detection. However, achieving high sensitivity and high specificity remains a challenge. Here, we perform a direct comparison of two droplet digital PCR (ddPCR)-based detection methods, circulating plasma tumor RNA and circulating plasma tumor DNA (ptDNA), in blood samples from newly diagnosed Ewing sarcoma patients. First, we developed three specific ddPCR-based assays to detect EWS-FLI1 or EWS-ERG fusion transcripts, which naturally showed superior sensitivity to DNA detection on in vitro control samples. Next, we identified the patient-specific EWS-FLI1 or EWS-ERG breakpoint from five patient tumor samples and designed ddPCR-based, patient-specific ptDNA assays for each patient. These patient-specific assays show that although plasma tumor RNA can be detected in select newly diagnosed patients, positive results are low and statistically unreliable compared with ptDNA assays, which reproducibly detect robust positive results across most patients. Furthermore, the unique disease biology of Ewing sarcoma enabled us to show that most cell-free RNA is not tumor-derived, although cell-free-DNA burden is affected strongly by tumor-derived DNA burden. Here, we conclude that, even with optimized highly sensitive and specific assays, tumor DNA detection is superior to RNA detection in Ewing sarcoma patients.

BACKGROUND: Acute hematogenous musculoskeletal infections are a common cause of hospitalization in children. A locally developed clinical care guideline (CCG) for acute musculoskeletal infections was implemented at our quaternary care pediatric hospital in July 2012. The purpose of this study was to evaluate the long-term sustainability of previously described improvements after CCG implementation. METHODS: Clinical outcomes for children hospitalized with musculoskeletal infections at Children’s Hospital Colorado from June 2009 through September 2018 were retrospectively reviewed. Patients were included if they had an International Classification of Diseases, Ninth Revision or International Classification of Diseases, 10th Revision discharge diagnosis of acute osteomyelitis, septic arthritis, or pyomyositis and were between 6 months and 18 years of age at admission. Patients with underlying medical complexity or nonhematogenous musculoskeletal infections were excluded. Patients were categorized by date of admission as either “pre-CCG” (June 2009 to June 2011) or “sustain-CCG” (July 2014 to September 2018). Primary outcomes were hospital length of stay and intravenous antimicrobial length of therapy. RESULTS: From pre-CCG to sustain-CCG, median length of stay decreased by 1.29 days (5.56 vs 4.27; P < .004) and median length of therapy decreased by 5.04 days (8.33 vs 3.29; P < .0001). Statistical process control charts support that these were sustained improvements many years after CCG implementation. Additional secondary clinical improvements were observed in the sustain-CCG group including faster fever resolution, more consistent blood and source culture acquisition, and decreased central line placement. There was no increase in related readmissions or therapeutic failures in the sustain-CCG group. CONCLUSIONS: Implementation of a CCG to standardize care for musculoskeletal infections can be sustained many years after implementation.

1. Nathan Donaldson, DO* 2. Julia Sanders, MD* 3. Jason Child, PharmD† 4. Sarah Parker, MD‡ 1. *Division of Orthopedic Surgery and 2. ‡Division of Infectious Diseases, Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO 3. †Department of Pharmacy, Children’s Hospital Colorado, Aurora, CO * Abbreviations: ADE: : adverse drug event CRMO: : chronic recurrent multifocal osteomyelitis CRP: : C-reactive protein CT: : computed tomography ESR: : erythrocyte sedimentation rate MRI: : magnetic resonance imaging MRSA: : methicillin-resistant Staphylococcus aureus MSSA: : methicillin-susceptible Staphylococcus aureus OAI: : osteoarticular infection WBC: : white blood cell Management of pediatric acute hematogenous osteoarticular infections has changed in various ways during the past decade, including the description of new pathogens and updated diagnostic and treatment strategies (such as infected source sampling and an early switch to oral therapy). After completing this article, readers should be able to: 1. Understand what predisposes children of different age groups to acute hematogenous osteoarticular infections (OAIs), particularly the role of anatomy and differing pathogenic susceptibilities. 2. Recognize the symptoms present in children with OAIs and their most common differential diagnoses. 3. Understand the most effective imaging techniques and laboratory tests/cultures to diagnose an OAI and how to interpret them. 4. Understand the benefits and limitations of therapeutic surgery and source sampling (biopsy/aspirate) and when to commence antimicrobial drug therapy. 5. Recognize the most common causative pathogens and the most effective antimicrobial drugs for their treatment. 6. Determine how long a patient should be taking intravenous and oral therapy and under what conditions they should switch from intravenous to oral antimicrobial agents. 7. Understand the recommended follow-up after diagnosis, including when to expect normalization of laboratory values in patients with uncomplicated OAIs. 8. Recognize complicated OAIs and their possible long-term sequelae. Pediatric osteoarticular infections (OAIs) include infections of the bones (osteomyelitis) and joints (septic arthritis). Pathogenic organisms may be introduced into these normally sterile sites via direct inoculation (eg, trauma or surgery) or via erosion from a contiguously infected source (eg, chronic ulcer), but organisms are mostly hematogenously delivered. Bacteria are the most common pathogens to cause OAIs, but mycobacteria, fungi, and viruses can also infect these tissues. If diagnosed in the first 10 to 14 days, these infections are …

The effects of radiation therapy and laminectomy on the growing spine have been well documented. Due to compromised bone quality after irradiation, spinal fusion has a high failure rate. The aim of this study was to evaluate treatment of post-laminectomy and post-irradiation kyphosis in children using a vascularized rib graft (VRG) to augment anterior spinal fusion and posterior spinal fusion. Data were collected retrospectively from electronic medical records for all patients treated at a single institution for post-laminectomy and post-irradiation kyphosis who underwent VRG to augment spinal fusions done between December 2003 and August 2015. Five patients were included in the analysis. Imaging studies were analyzed by 2 senior pediatric orthopedic surgeons and a pediatric orthopedic surgery fellow. The outcome for all 5 patients who underwent VRG were considered successful at most recent clinical follow-up. Success was defined as the following: complete fusion evident through computed tomography scan, no implant failure, and no kyphosis progression. Follow-up ranged from 21 to 63 months. One patient experienced 2 complications: esophageal tear and deep infection. Spinal fusion with a VRG is a viable treatment option for children who have developed kyphosis following laminectomy and irradiation. On long-term follow-up, there has been no evidence of progression of kyphosis for patients who were treated with VRG in either the primary fusion procedure or in subsequent revision procedures. A VRG provides a non-irradiated, vascularized bone graft to bridge the irradiated segments, increasing the stability of the spine. [ Orthopedics . 2021;44(4):e563–e569.]

Background Acute pediatric musculoskeletal infections are common, leading to significant use of resources and antimicrobial exposure. In order to decrease variability and improve the quality of care, Children's Hospital Colorado implemented a clinical care guideline (CCG) for these infections. The purpose of this study is to evaluate clinical and resource outcomes PRE and POST this CCG. Methods Retrospective chart review evaluated patients admitted to a large pediatric quaternary referral center (CHCO) diagnosed with acute osteomyelitis, septic arthritis, pyomyositis, and/or musculoskeletal abscess prior to and after guideline implementation. Primary outcomes included length of stay and overall antibiotic use, with additional secondary clinical, process, and therapeutic outcomes examined. Results 82 patients were identified in both the pre-CCG and post-CCG cohorts. There was a reduction in the median of all primary outcomes, including length of stay (0.6 median days decrease, P = .04), length of IV antibiotic therapy (4.9 median days decrease, P < .0001), and days of IV antibiotic therapy (6.4 median days decrease, P = .0004). Our median length of stay post-CCG was 4.9 days, the shortest reported length of stay for pediatric acute musculoskeletal infections to date. Additionally, there was a 24.5 hour reduction in median length of fever (P = .02), faster CRP normalization (P < .0001), 50% decrease in the number of related readmissions (P = .02), 34% decrease in central venous catheters placed (P < .0001), decreased time to first culture (P = .02), and 79% pathogen identification post-CCG (P = .056). Conclusions Implementation of a CCG for acute musculoskeletal infections improves patient, process and resource outcomes.

Case A 19-year-old adolescent with Kniest dysplasia was incidentally found to have osteosarcoma of the proximal aspect of the humerus after having a chest radiograph for evaluation of an upper respiratory infection. He underwent chemotherapy and resection of the tumor, and there was no evidence of metastasis at the 16-month follow-up. Conclusion Patients with osteochondrodysplasias often have multiple orthopaedic symptoms. Changes in chronic pain symptoms should be investigated to rule out insidious secondary causes of musculoskeletal pain, such as osteosarcoma.

Background Pathogen detection in pediatric patients with musculoskeletal infections relies on conventional bacterial culture, which is slow and can delay antimicrobial optimization. The ability to rapidly identify causative agents and antimicrobial resistance genes in these infections may improve clinical care. Methods Convenience specimens from bone and joint samples submitted for culture to Children's Hospital Colorado (CHCO) from June 2012 to October 2016 were evaluated using a “Musculoskeletal Diagnostic Panel” (MDP) consisting of the Xpert MRSA/SA SSTI real-time PCR (qPCR, Cepheid) and laboratory-developed qPCRs for Kingella kingae detection and erm genes A, B, and C which confer clindamycin resistance. Results from the MDP were compared to culture and antimicrobial susceptibility testing (AST) results. Results A total of 184 source specimens from 125 patients were tested. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the Xpert MRSA/SA SSTI compared to culture and AST results were 85%, 98%, 93%, and 95% respectively for MSSA and 82%, 100%, 100%, and 99% for MRSA. Compared to phenotypic clindamycin resistance in S. aureus isolates, the erm A, B, and C gene PCRs collectively demonstrated a sensitivity, specificity, PPV, and NPV of 80%, 96%, 67%, and 98%. In comparison to clinical truth, Kingella PCR had a sensitivity, specificity, PPV, and NPV of 100%, 99.5%, 100%, and 100%. Conclusions This novel MDP offers a rapid, sensitive, and specific option for pathogen detection in pediatric patients with musculoskeletal infections.

Background High-dose-rate brachytherapy (HDR-BT) and external-beam radiation therapy (EBRT) are two modalities used in the treatment of soft tissue sarcoma. Previous work at our institution showed early complications and outcomes for patients treated with HDR-BT, EBRT, or a combination of both radiation therapy modalities. As the general indications for each of these approaches to radiation therapy differ, it is important to evaluate the use of each in an algorithmic way, reflecting how they are used in contemporary practice at sites that use these treatments. QUESTION/PURPOSES: (1) To determine the proportions of intermediate- and long-term complications associated with the use of brachytherapy in the treatment of primary high-grade extremity soft tissue sarcomas; (2), to characterize the long-term morbidity of the three radiation treatment groups using the Radiation Therapy Oncology Group/ European Organization for Research and Treatment of Cancer (RTOG/EORTC) Late Radiation Morbidity Scoring Scheme; (3) to determine whether treatment with HDR-BT, EBRT, and HDR-BT+EBRT therapy, in combination with limb-salvage surgery, results in acceptable local control in this high-risk group of sarcomas. Methods We retrospectively studied data from 171 patients with a diagnosis of high-grade extremity soft tissue sarcoma treated with limb-sparing surgery and radiation therapy between 1990 and 2012 at our institution, with a mean followup of 72 months. Of the 171 patients, 33 (20%) were treated with HDR-BT, 128 (75%) with EBRT, and 10 (6%) with HDR-BT+EBRT. We excluded 265 patients with soft tissue sarcomas owing to axial tumor location, previous radiation to the affected extremity, incomplete patient records, patients receiving primary amputation, recurrent tumors, pediatric patients, low- and intermediate-grade tumors, and rhabdoid histology. Fifteen patients (9%) were lost to followup for any reason including died of disease or other causes during the first 12 months postoperatively. This included four patients who received HDR-BT (12%), 11 who received EBRT (9%), and none who received HDR-BT+EBRT (0%) with less than 12 months followup. Determination of radiation therapy technique for each patient was individualized in a multidisciplinary forum of sarcoma specialists. Anticipated close or positive surgical margins and a low likelihood of complex soft tissue procedures were factors that encouraged use of brachytherapy, whereas the anticipated need for secondary procedures and/or soft tissue coverage encouraged use of EBRT alone. Combination therapy was used when the treatment volume exceeded the treatment field of the brachytherapy catheters or when the catheters were used to boost a close or positive surgical margin. Local recurrence, complications, and morbidity outcomes scores (RTOG) were calculated based on chart review. Between-group comparisons pertaining to the proportion of patients experiencing complications, morbidity outcomes scores, and local recurrence rates were not performed because of dissimilarities among the patients in each group at baseline. Results The HDR-BT treatment group showed a high incidence of intermediate-term complications, with the three most common being: deep infection (33%, 11 of 33); dehiscence and delayed wound healing (24%, eight of 33); and seroma and hematoma (21%, seven of 33). The EBRT group showed a high incidence of intermediate- and long-term complications with the three most common being: chronic radiation dermatitis (35%, 45 of 128); fibrosis (27%, 35 of 128); and chronic pain and neuritis (13%, 16 of 128). The RTOG scores for each treatment group were: HDR-BT 0.8 ± SD 1.2; EBRT 1.9 ± 2.0; and HDR-BT+EBRT 1.7 ± 1.7. Overall, 142 of 169 (84%) patients were free from local recurrence: 27 (82%) in the HDR-BT group, 108 (86%) in the EBRT group, and seven (70%) in the combination therapy group. Conclusions In this single-institution study, an algorithmic approach to using HDR-BT and EBRT in the treatment of patients with high-grade soft tissue sarcomas can yield acceptable complication rates, good morbidity outcome scores, and a high degree of local control. Based on these results, we believe HDR-BT is best for patients with an anticipated close margin, a positive surgical margin, and for patients who are unlikely to receive a complex soft tissue procedure. Conversely, if a secondary procedure and/or soft tissue coverage are likely to be used, EBRT alone may be reasonable. Finally, combination therapy might be considered when the treatment volume exceeded the treatment field capacity for HDR-BT or when the catheters were used to boost a close or positive surgical margin. Level of evidence Level IV, therapeutic study.

Patients with congenital pseudarthrosis of the tibia do not have a normal tibia. In such patients, the entire tibia is abnormal (even outside of the established pseudarthrosis site); the bone does not have a normal healing response to injury or osteotomy, and the proximal growth plate typically has

Solid organ transplant recipients are at increased risk of malignancy. Pediatric transplant recipients particularly have a potentially higher risk given the young age of immunosuppression initiation. Posttransplant malignancies are the main cause of death in 5%–16% of liver transplantation patients. The frequency of de novo malignancies in pediatric liver transplant recipients has been reported to be 13%. Synovial sarcoma is a malignant mesenchymal neoplasm that has not been previously reported after liver transplantation. We report the case of an adolescent liver transplant recipient who was diagnosed with synovial sarcoma 14 years after liver transplantation.

Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) are a heterogeneous group of sarcomas that encompass over 35 histologies. With an incidence of ∼500 cases per year in the United States in those20 years of age, NRSTS are rare and therefore difficult to study in pediatric populations. We used the large Surveillance, Epidemiology, and End Results (SEER) database to validate the prognostic ability of the Children's Oncology Group (COG) risk classification system and to define patient, tumor, and treatment characteristics.From SEER data from 1988 to 2007, we identified patients ≤18 years of age with NRSTS. Data for age, sex, year of diagnosis, race, registry, histology, grade, primary size, primary site, stage, radiation therapy, and survival outcomes were analyzed. Patients with nonmetastatic grossly resected low-grade tumors of any size or high-grade tumors ≤5 cm were considered low risk. Cases of nonmetastatic tumors that were high grade,5 cm, or unresectable were considered intermediate risk. Patients with nodal or distant metastases were considered high risk.A total of 941 patients met the review criteria. On univariate analysis, black race, malignant peripheral nerve sheath (MPNST) histology, tumors5 cm, nonextremity primary, lymph node involvement, radiation therapy, and higher risk group were associated with significantly worse overall survival (OS) and cancer-specific survival (CSS). On multivariate analysis, MPNST histology, chemotherapy-resistant histology, and higher risk group were significantly poor prognostic factors for OS and CSS. Compared to low-risk patients, intermediate patients showed poorer OS (hazard ratio [HR]: 6.08, 95% confidence interval [CI]: 3.53-10.47, P.001) and CSS (HR: 6.27; 95% CI: 3.44-11.43, P.001), and high-risk patients had the worst OS (HR: 13.35, 95% CI: 8.18-21.76, P.001) and CSS (HR: 14.65, 95% CI: 8.49-25.28, P.001).The current COG risk group stratification for children with NRSTS has been validated with a large number of children in the SEER database.