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.

Background Genomic tumor profiling (GTP) plays an important role in the care of many adult cancer patients. Its role in pediatric oncology is still evolving, with only a subset of patients currently expected to receive clinically significant results. Little is known about perspectives of pediatric oncology patients/parents on GTP. Procedure We surveyed individuals who previously underwent GTP through the iCat (Individualized Cancer Therapy) pilot study of molecular profiling in children with relapsed, refractory, and high-risk solid tumors at four pediatric cancer centers. Following return of profiling results, a cross-sectional survey was offered to the patient, if ≥18y at enrollment, or parent, if <18y. Forty-five surveys (85% response) were completed. Results Eighty-nine percent (39/44) of respondents reported hoping participation would help find cures for future patients, while 59% (26/44) hoped it would increase their/their child’s chance of cure. Most had few concerns about GTP, but 12% (5/43) worried they would learn their/their child’s cancer was less treatable or more aggressive than previously thought. Sixty-four percent (29/45) reported feeling their participation had helped others, and 44% (20/45) felt they had helped themselves/their own child, despite only one sub-study subject receiving targeted therapy matched to GTP findings. Fifty-four percent (21/39) wished to receive all available profiling data, including findings unrelated to cancer and of unclear significance. Conclusions Participants in pediatric GTP research perceive benefits of GTP to themselves and others, but expectations of personal benefits of GTP may exceed actual positive impact. These issues warrant consideration during consent discussions about GTP research participation.

Identifying therapeutic targets in rare cancers remains challenging due to the paucity of established models to perform preclinical studies. As a proof-of-concept, we developed a patient-derived cancer cell line, CLF-PED-015-T, from a paediatric patient with a rare undifferentiated sarcoma. Here, we confirm that this cell line recapitulates the histology and harbours the majority of the somatic genetic alterations found in a metastatic lesion isolated at first relapse. We then perform pooled CRISPR-Cas9 and RNAi loss-of-function screens and a small-molecule screen focused on druggable cancer targets. Integrating these three complementary and orthogonal methods, we identify CDK4 and XPO1 as potential therapeutic targets in this cancer, which has no known alterations in these genes. These observations establish an approach that integrates new patient-derived models, functional genomics and chemical screens to facilitate the discovery of targets in rare cancers.

PD by RECIST predicts poor outcome in localized disease patients. In bone lesions, chemotherapy proven to improve overall survival does not result in radiographic responses as measured by RECIST. Further investigation of RECIST in pulmonary metastatic disease in osteosarcoma is needed.

Health care personnel (HCP) are at increased risk for infection with SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), as a result of their exposure to patients or community contacts with COVID-19 (1,2). Since the first confirmed case of COVID-19 in Minnesota was reported on March 6, 2020, the Minnesota Department of Health (MDH) has required health care facilities* to report HCP † exposures to persons with confirmed COVID-19 for exposure risk assessment and to enroll HCP with higher-risk exposures into quarantine and symptom monitoring. During March 6-July 11, MDH and 1,217 partnering health care facilities assessed 21,406 HCP exposures; among these, 5,374 (25%) were classified as higher-risk § (3). Higher-risk exposures involved direct patient care (66%) and nonpatient care interactions (e.g., with coworkers and social and household contacts) (34%). Within 14 days following a higher-risk exposure, nearly one third (31%) of HCP who were enrolled in monitoring reported COVID-19-like symptoms, ¶ and more than one half (52%) of enrolled HCP with symptoms received positive * Health care facilities as defined by MDH include acute care hospitals, critical access hospitals, long-term acute care hospitals, skilled nursing facilities, assisted living facilities, group homes, adult foster care, treatment facilities, dialysis centers, outpatient clinics, dental clinics, home health care, and hospice. † HCP as defined by MDH include, but are not limited to, emergency medical service personnel, nurses, nursing assistants, physicians, technicians, therapists, phlebotomists, pharmacists, students and trainees, contractual staff members not employed by the health care facility, and persons not directly involved in patient care, but who could be exposed to infectious agents that can be transmitted in the health care setting (e.g., clerical, dietary, environmental services, laundry, security, engineering and facilities management, administrative, billing, and volunteer personnel). HCP does not include clinical laboratory personnel. § During February 8-May 18, 2020, CDC exposure risk assessment guidance included medium-and high-risk categories, with risk level based on PPE worn and type of potential contact with a person with confirmed COVID-19. On May 19, CDC's risk assessment was updated to include a single higher-risk exposure category to include close (within 6 feet), prolonged (≥15 minutes or of any duration during an aerosol-generating procedure) contact with a person with confirmed COVID

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Purpose Increasing use of genomic tumor profiling may blur the line between research and clinical care. We aimed to describe perspectives of research participants about the purpose of genomic tumor profiling research in pediatric oncology. Methods We surveyed 45 participants (response rate, 85%) in a pilot study of genomic profiling in pediatric solid tumors at four academic cancer centers after the return of sequencing results. We defined understanding according to a one-item (basic) definition (recognition that the primary purpose was not to improve the patient’s treatment) and a four-item (comprehensive) definition (primary purpose was not to improve patient’s treatment; primary purpose was to improve treatment of future patients; there may not be direct medical benefit; most likely result of participation was not increased likelihood of cure). Results Sixty-eight percent of respondents (30 of 44 respondents) demonstrated basic understanding of the study purpose; 55% (24 of 44 respondents) demonstrated comprehensive understanding. Understanding was more frequently seen in those with higher education and greater genetic knowledge according to basic (81% v 50% [ P = .05]; and 82% v 46% [ P = .03], respectively) and comprehensive (73% v 28% [ P = .01]; 71% v 23% [ P = .01]) definitions. Ninety-three percent of respondents who believed the primary purpose was to improve the patient’s care simultaneously stated that the research also aimed to benefit future patients. Conclusion Most participants in pediatric tumor profiling research understand that the primary goal of this research is to improve care for future patients, but many express dual goals when they participate in sequencing research. Some populations demonstrate increased rates of misunderstanding. Nuanced participant views suggest that additional work is needed to assess and improve participant understanding, particularly as tumor sequencing moves beyond research and into clinical practice.

Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies in a systematic manner remains challenging in part due to the lack of faithful preclinical in vitro models. We established ten short-term patient-derived WT cell lines and characterized these models using low-coverage whole genome sequencing, whole exome sequencing and RNA-sequencing, which demonstrated that these ex-vivo models faithfully recapitulate WT biology. We then performed targeted RNAi and CRISPR-Cas9 loss-of-function screens and identified the nuclear export genes (XPO1 and KPNB1) as strong vulnerabilities. We observed that these models are sensitive to nuclear export inhibition using the FDA approved therapeutic agent, selinexor (KPT-330). Selinexor treatment of FHWT suppressed TRIP13 expression, which was required for survival. We further identified in vitro and in vivo synergy between selinexor and doxorubicin, a chemotherapy used in high risk FHWT. Taken together, we identified XPO1 inhibition with selinexor as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.