Correction: Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group.

The authors have noticed that the final paragraph of the Results section contains errors in the number of patients involved. The correct number of patients is included in the text below. These errors do not affect the Figure referenced.In osteosarcoma, we focused on 8q gain as a specific biological feature of interest. Among the 41 patients with detectable ctDNA in the osteosarcoma cohort, 8q gain was detected in 73.2% (30/41). The 3-year EFS for patients with 8q gain (n = 30) in ctDNA was 60.0% (95% CI 40.5-75.0) compared to 80.8 (95% CI 42.4-94.9) in patients without 8q gain (n = 11) in ctDNA (p = 0.18; Fig. 3).

Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group.

BACKGROUND: New prognostic markers are needed to identify patients with Ewing sarcoma (EWS) and osteosarcoma unlikely to benefit from standard therapy. We describe the incidence and association with outcome of circulating tumour DNA (ctDNA) using next-generation sequencing (NGS) assays. METHODS: A NGS hybrid capture assay and an ultra-low-pass whole-genome sequencing assay were used to detect ctDNA in banked plasma from patients with EWS and osteosarcoma, respectively. Patients were coded as positive or negative for ctDNA and tested for association with clinical features and outcome. RESULTS: The analytic cohort included 94 patients with EWS (82% from initial diagnosis) and 72 patients with primary localised osteosarcoma (100% from initial diagnosis). ctDNA was detectable in 53% and 57% of newly diagnosed patients with EWS and osteosarcoma, respectively. Among patients with newly diagnosed localised EWS, detectable ctDNA was associated with inferior 3-year event-free survival (48.6% vs. 82.1%; p = 0.006) and overall survival (79.8% vs. 92.6%; p = 0.01). In both EWS and osteosarcoma, risk of event and death increased with ctDNA levels. CONCLUSIONS: NGS assays agnostic of primary tumour sequencing results detect ctDNA in half of the plasma samples from patients with newly diagnosed EWS and osteosarcoma. Detectable ctDNA is associated with inferior outcomes.

A case of parasympathetic hyperactivity and associated Parry-Romberg syndrome.

This case report describes a 46-year-old female with a history of multiple endocrine neoplasia type 1 syndrome status post-parathyroidectomy, thymectomy via robotic video-assisted thoracoscopic surgery, and pituitary adenoma resection presenting with parasympathetic hyperactivity and Parry-Romberg syndrome. Parry-Romberg syndrome is a rare disorder that manifests as facial hemiatrophy. Reported symptoms include cognitive dysfunction, olfactory hallucinations, and parasympathetic hyperactivity: miosis of the right eye, anhidrosis, diarrhea, urinary incontinence, bowel incontinence, and orthostatic hypotension. Previous reports have noted associations between Parry-Romberg syndrome and sympathetic hyperactivity and dysregulation. This case report focuses on an association between Parry-Romberg syndrome and unopposed parasympathetic activity.

Detection of Somatic Structural Variants Enables Quantification and Characterization of Circulating Tumor DNA in Children With Solid Tumors.

Objective: Liquid biopsies are being rapidly used in adult cancers as new biomarkers of disease. Circulating tumor DNA (ctDNA) levels have been reported to be proportional to disease burden, correlate with treatment response, and predict relapse. However, little is known about how frequently ctDNA is detectable in pediatric patients with solid tumors. Therefore, we developed a next-generation sequencing approach to detect and quantify ctDNA in the blood of patients with the most common pediatric solid tumors. Methods: Detection of ctDNA requires assays sensitive to somatic events typically observed in the cancer type being studied. In pediatric solid tumors, structural variants are more common than recurrent point mutations. We adapted an ultralow passage whole-genome sequencing approach to capture copy number variants and a hybrid capture sequencing assay to detect translocations in liquid biopsy samples from pediatric patients. Results: Copy number changes seen by ultralow passage whole-genome sequencing enabled detection of ctDNA in patients with osteosarcoma, neuroblastoma, alveolar rhabdomyosarcoma, and Wilms tumor. In Ewing sarcoma, detection of the EWSR1 translocation was a more sensitive approach. For patients with samples collected at multiple time points, changes in ctDNA levels corresponded to treatment response. We also found that disease-specific genomic biomarkers of prognosis were detectable in ctDNA. Conclusion: This study demonstrates that liquid biopsy approaches that detect somatic structural variants are well suited to pediatric solid tumors. We show that children with the most common solid tumor malignancies have detectable levels of ctDNA, which may be used to track disease response and identify genomic subclassifiers of disease. Efforts to profile larger collections of clinically annotated specimens are under way to validate the clinical use of these assays.

Blood collection in cell-stabilizing tubes does not impact germline DNA quality for pediatric patients.

OBJECTIVES: Liquid biopsy technologies allow non-invasive tumor profiling for patients with solid tumor malignancies by sequencing circulating tumor DNA. These studies may be useful in risk-stratification, monitoring for relapse, and understanding tumor evolution. The quality of DNA obtained for these studies is improved when blood samples are collected in tubes that stabilizing white blood cells (WBC). However, ongoing germline research in pediatric oncology generally requires obtaining blood samples in EDTA tubes, which do not contain a WBC-stabilizing preservative. In this study, we explored whether blood samples collected in WBC-stabilizing tubes could be used for both liquid biopsy and germline studies simultaneously, minimizing blood collection volumes for pediatric patients. METHODS: Blood was simultaneously collected from three patients in both EDTA and Streck Cell-Free DNA BCT® tubes. Germline DNA was extracted from all blood samples and subjected to whole-exome sequencing and microarray profiling. RESULTS: Quality control metrics of DNA quality, sequencing library preperation and whole-exome sequencing alignment were virtually identical regardless of the sample collection method. There was no discernable difference in patterns of variant calling for paired samples by either whole-exome sequencing or microarray analysis. CONCLUSION: Our study demonstrates that high-quality genomic studies may be performed from germline DNA obtained in Streck tubes. Therefore, these tubes may be used to simultaneously obtain samples for both liquid biopsy and germline studies in pediatric patients when the volume of blood available for research studies may be limited.