Children's Oncology Group's 2023 blueprint for research: Soft tissue sarcomas.

In the United States, approximately 850-900 children and adolescents each year are diagnosed with soft tissue sarcomas (STS). STS are divided into rhabdomyosarcoma (RMS) and non-rhabdomyosarcoma STS (NRSTS). RMS and NRSTS are risk stratified into low-, intermediate-, and high-risk categories, with 5-year survival rates of approximately 90%, 50%-70%, and 20%, respectively. Recent key achievements from the Children's Oncology Group (COG) STS Committee include the identification of new molecular prognostic factors for RMS, development and validation of a novel risk stratification system for NRSTS, successful completion of a collaborative NRSTS clinical trial with adult oncology consortia, and collaborative development of the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT). Current COG trials for RMS are prospectively evaluating a new risk stratification system that incorporates molecular findings, de-intensification of therapy for a very low-risk subgroup, and augmented therapy approaches for intermediate- and high-risk RMS. Trials for NRSTS exploring novel targets and local control modalities are in development.

Patients with completely resected nongenitourinary low-risk embryonal rhabdomyosarcoma are candidates for reduced duration low-intensity chemotherapy.

BACKGROUND: The survival of patients with localized embryonal rhabdomyosarcoma (RMS) completely resected at diagnosis is greater than 90%. Most patients have paratesticular, uterine, or vaginal RMS, limiting specific analyses of RMS localized in other anatomic regions. This international study was conducted to define the outcome for completely resected embryonal RMS at sites other than paratesticular, uterine, or vaginal primary sites. METHODS: A total of 113 patients aged 0-18 years were identified who were enrolled from January 1995 to December 2016 in Children's Oncology Group (COG) (64 patients) and European protocols (49). Genitourinary nonbladder and prostate RMS were excluded. The recommended chemotherapy was vincristine and actinomycin-D (VA) for 24 weeks or ifosfamide plus VA in the European protocols and VA for 48 weeks or VA plus cyclophosphamide in the COG protocols. RESULTS: The most common primary sites were nonparameningeal head and neck (40.7%), other (23.9%), and extremities (20.4%). In the COG studies, 42% of patients received VA and 58% VA plus cyclophosphamide. In Europe, 53% received VA and 47% ifosfamide plus VA. With a median follow-up of 97.5 months, the 5-year progression-free and overall survival was 80.0% (71.2%-86.4%) and 92.5% (85.6%-96.2%), respectively, without significant differences between chemotherapy regimens. Tumor size (< or >5 cm) significantly influenced overall survival: 96.2% (88.6%-98.8%) vs. 80.6% (59.5%-91.4%), respectively (p = .01). CONCLUSIONS: Survival of patients with nonalveolar RMS completely resected at diagnosis is excellent among tumors arising from nonparatesticular, uterine, and vaginal sites, and patients may be treated successfully with low-intensity chemotherapy. To reduce the burden of treatment, VA for 24 weeks may be considered in children with tumors <5 cm.

An update on rhabdomyosarcoma risk stratification and the rationale for current and future Children's Oncology Group clinical trials.

Children and adolescents with rhabdomyosarcoma (RMS) comprise a heterogeneous population with variable overall survival rates ranging between approximately 6% and 100% depending on defined risk factors. Although the risk stratification of patients has been refined across five decades of collaborative group studies, molecular prognostic biomarkers beyond FOXO1 fusion status have yet to be incorporated prospectively in upfront risk-based therapy assignments. This review describes the evolution of risk-based therapy and the current risk stratification, defines a new risk stratification incorporating novel biomarkers, and provides the rationale for the current and upcoming Children's Oncology Group RMS studies.

The Use of Continuous Veno-Venous Hemodiafiltration in the Management of Ifosfamide-induced Encephalopathy: A Case Report.

Encephalopathy is a common side effect of ifosfamide, occurring in up to 30% of patients. Although self-resolving in most cases, death secondary to severe encephalopathy has been reported. Methylene blue and thiamine have been occasionally successful as treatment. We report a case of an 11-year-old girl with relapsed neuroblastoma who developed grade 4 ifosfamide-induced encephalopathy. She showed no initial response to methylene blue and thiamine. She remained neurologically impaired and continuous veno-venous hemodiafiltration was started, with rapid resolution of encephalopathy. This is the first report of continuous veno-venous hemodiafiltration use for suspected ifosfamide-induced encephalopathy in the pediatric population.

Interaction between bone marrow stromal cells and neuroblastoma cells leads to a VEGFA-mediated osteoblastogenesis.

The potential role of osteoblasts in bone and bone marrow (BM) metastases in neuroblastoma (NBL) remains unclear. In this study, we examined the effect of NBL cells on the osteoblastic differentiation of BM-derived mesenchymal stromal cells (BMMSC). We show that the presence of NBL cells enhanced the osteoblastic differentiation of BMMSC driven by bone morphogenetic protein (BMP)-4, in the absence of any effect on NBL cell proliferation. Expression profiles of BMMSC driven toward osteoblastic differentiation revealed an increase in vascular endothelial growth factor A (Vegfa) expression in the presence of NBL cells. We demonstrated that NBL cells increased BMMSC-derived VEGFA mRNA and protein and that this was enhanced by BMP-4. However, in similar conditions, neither the addition of an mVEGFA blocking antibody nor exogenous recombinant (r) mVEGFA affected osteoblastic differentiation. In contrast, siRNA- mediated knock-down of VEGFA in BMMSC prevented osteoblastic differentiation in BMP-4-treated cocultures, an effect that was not reversed in the presence of rmVEGFA. An analysis of murine bones injected with hNBL cells revealed an increase of mVEGFA producing cells near tumor cells concomitantly with an increase in Vegfa and Runx2 mRNA. This coincided with an increase in osteoclasts, in Rankl/Opg mRNA ratio and with the formation of osteolytic lesions. Thus NBL cells promote osteoblastogenesis in the BM by increasing VEGFA expression in BMMSC. Our study provides a new insight into the role of VEGFA in NBL metastases by pointing to the role of stroma-derived intracrine VEGFA in osteoblastogenesis.

Sarcomas.

Malignant bone tumors (osteosarcoma, Ewing sarcoma) and soft-tissue sarcomas (rhabdomyosarcoma, nonrhabdomyosarcoma) account for approximately 14% of childhood malignancies. Successful treatment of patients with sarcoma depends on a multidisciplinary approach to therapy, including oncology, surgery, radiation oncology, radiology, pathology, and physiatry. By combining systemic treatment with chemotherapy and primary tumor control using surgery and/or radiation, survival rates for localized disease range from 70% to 75%. However, children with metastatic or recurrent disease continue to have dismal outcomes. A better understanding of the biology underlying both bone and soft-tissue sarcomas is required to further improve outcomes for children with these tumors.

Notch signaling is antagonized by SAO-1, a novel GYF-domain protein that interacts with the E3 ubiquitin ligase SEL-10 in Caenorhabditis elegans.

Notch signaling pathways can be regulated through a variety of cellular mechanisms, and genetically compromised systems provide useful platforms from which to search for the responsible modulators. The Caenorhabditis elegans gene aph-1 encodes a component of γ-secretase, which is essential for Notch signaling events throughout development. By looking for suppressors of the incompletely penetrant aph-1(zu147) mutation, we identify a new gene, sao-1 (suppressor of aph-one), that negatively regulates aph-1(zu147) activity in the early embryo. The sao-1 gene encodes a novel protein that contains a GYF protein-protein interaction domain and interacts specifically with SEL-10, an Fbw7 component of SCF E3 ubiquitin ligases. We demonstrate that the embryonic lethality of aph-1(zu147) mutants can be suppressed by removing sao-1 activity or by mutations that disrupt the SAO-1-SEL-10 protein interaction. Decreased sao-1 activity also influences Notch signaling events when they are compromised at different molecular steps of the pathway, such as at the level of the Notch receptor GLP-1 or the downstream transcription factor LAG-1. Combined analysis of the SAO-1-SEL-10 protein interaction and comparisons of sao-1 and sel-10 genetic interactions suggest a possible role for SAO-1 as an accessory protein that participates with SEL-10 in downregulation of Notch signaling. This work provides the first mutant analysis of a GYF-domain protein in either C. elegans or Drosophila and introduces a new type of Fbw7-interacting protein that acts in a subset of Fbw7 functions.