Citations

ABSTRACT Background and Objectives Non‐rhabdomyosarcoma soft tissue sarcomas (NRSTS) account for less than 4% of pediatric cancers. Treatment and outcomes have been described in adults, but pediatric data are lacking. The purpose of this study is to review our institution's outcomes of extremity NRSTS in pediatric patients. Methods Ninety‐eight (56 male: 42 female) pediatric patients with NRSTS of the extremity at our institution were reviewed. Mean age at diagnosis was 11 ± 5 years, and mean follow‐up was 12 ± 10 years. The most common diagnosis was synovial sarcoma (27%), and 60% were high‐grade. Results Treatment included surgical resection in all patients, with 33% receiving radiation and 37% receiving systemic therapy. 20‐year local recurrence‐ (LRFS) and metastatic disease‐free survival (MDFS) were 91% and 91%, respectively, with 92% disease specific survival (DSS). High grade tumors were associated with lower LRFS ( p = 0.02) and DSS ( p = 0.03). Tumor size < 5 cm demonstrated improved MDFS ( p = 0.03), and stage 3 tumors showed worse MDFS ( p < 0.01). Conclusions Treatment of pediatric NRSTS was variable, with large, deep, high‐grade tumors more likely to receive neoadjuvant and adjuvant treatments. Multidisciplinary treatment was associated with high rates of local control and durable survival. This study provides an extended follow‐up of pediatric patients to identify late complications.

Objective: This single institutional analysis explored outcomes and factors associated with local control and survival in pediatric patients with nonrhabdomyosarcoma soft tissue sarcoma (NRSTS). Methods: Patients 18 years of age or younger diagnosed between October 1990 and November 2021 who received external beam radiotherapy (EBRT) were retrospectively identified. Overall survival (OS) and disease-free survival (DFS) were analyzed using Kaplan-Meier methods and univariate Cox models. Results: Among 51 included patients, there were 33 extremity tumors (65%), with 80% T1/T2 and 90% M0. Surgery in 49/51 (96%) resulted in 32 (65%) R0 resections. All received EBRT, with brachytherapy or intraoperative radiotherapy boosts in 21/51 (41%). Thirty-four (66.7%) received chemotherapy. With 5.7 years median follow-up, 5-year OS and DFS were 70.7% and 67.9%, respectively. Positive margins were significantly associated with worse OS. Two-year local failure incidence was 18.1% for EBRT versus 5.3% for EBRT+boost (HR 3.67, P =0.24). Among 6 local failures, 5 received EBRT alone, including 3 with positive margins. Two treated with EBRT+boost had positive margins, neither with local recurrence. Conclusion: Multimodality treatment of pediatric NRSTS results in 5-year OS and DFS around 70%. Although complete resection remains essential, and the modern incidence of R1 resection has declined, IORT/brachytherapy boost may continue to have a role in selected patients with a high local recurrence risk.

Abstract Embryonal tumors with multilayered rosettes (ETMR) are rare, highly aggressive tumors of infancy with extremely poor outcomes and no established standard of care therapy. ETMRs were recognized as a distinct molecular entity in 2016, however, the absence of prospective, biology-driven clinical trials has limited translation of these insights into standardized, risk-adapted treatment approaches for this vulnerable population. To address this gap, the Collaborative Network for Neuro-oncology Clinical Trials (CONNECT) developed CURE(Clinical trial advancing Understanding of Rare Embryonal Brain Tumors), an international, multi-institutional, molecularly guided umbrella trial. All patients enroll through the centralized CURE-Screening protocol, which provides rapid comprehensive molecular profiling with real-time central pathology, molecular, and radiographic review to confirm diagnosis, define molecular subtype, and determine eligibility and assignment to disease-specific treatment arms. CURE-ETMR represents the first disease-specific arm to open within this platform. Following centralized screening, children with newly diagnosed ETMR are assigned to clinically defined risk strata using integrated molecular, radiographic, and clinical criteria. Patients will be treated using a risk-adapted multimodal approach in which we prioritize maximal safe surgical resection with consideration of second-look surgery based on centralized imaging review; administer induction chemotherapy followed by consolidation with high-dose chemotherapy and autologous hematopoietic cell rescue or dose-intensified chemotherapy, selectively incorporate radiation sparing approach or early focal radiotherapy for patients with unresectable residual disease or brainstem involvement; deliver intrathecal chemotherapy for leptomeningeal prophylaxis; and include biologically informed maintenance therapy. In parallel, protocol-required longitudinal collection of tumor tissue, cerebrospinal fluid, blood, and advanced neuroimaging supports integrated molecular, liquid biopsy, and imaging biomarker analyses to identify predictors of treatment response, resistance, and relapse. Primary objectives include evaluation of feasibility, safety, progression-free survival, and overall survival compared with molecularly annotated historical cohorts. This centralized screening to assignment framework establishes a scalable model for prospective, biology-driven trials in rare embryonal brain tumors.

Abstract Background Vorasidenib is Food and Drug Administration‐approved for treatment of grade 2 isocitrate dehydrogenase (IDH)–mutant gliomas and has demonstrated a benefit in progression‐free survival compared to a placebo. This study assessed the cost‐effectiveness of this treatment strategy compared to standard treatment: observation or chemoradiation (CRT). Methods The authors used an integrated Markov model to compare quality‐adjusted life‐years (QALY) gained and cost‐effectiveness of patients with IDH‐mutated low‐grade glioma (LGG) treated with vorasidenib, observation, or CRT. Outcomes were expressed as incremental cost‐effectiveness ratios (ICERs) per QALY gained. Treatment is considered cost‐effective if it meets the commonly accepted willingness‐to‐pay threshold of $100,000 per QALY gained. Results Based on model parameters, vorasidenib demonstrated an ICER of $356,756 per QALY when compared to CRT. When compared to observation, vorasidenib demonstrated an improved ICER of $215,191 per QALY. On one‐way sensitivity analysis compared to observation, median cost of vorasidenib and median overall survival were most likely to affect ICER with only marginal changes on analysis of other model factors. For ICER to become ≤$100,000 compared to observation, the cost of vorasidenib would need to drop to below $14,072 monthly or have a median survival gain of at least 11.9 years. The probabilistic sensitivity analysis demonstrated that vorasidenib was favored in none of 5000 Monte Carlo iterations. Conclusion Using the best available data, the current price of vorasidenib does not meet commonly accepted cost‐effectiveness thresholds in treatment of IDH‐mutated LGGs.

Abstract Background: Pediatric and AYA sarcomas are rare, biologically heterogeneous tumors with limited noninvasive biomarkers to guide diagnosis, personalized treatment, and disease monitoring. Standard-of-care evaluation relies on invasive biopsies that carry procedural risks and imaging modalities with limited sensitivity for detecting minimal residual disease and distinguishing tumor types. Cell-free DNA (cfDNA) methylation profiling offers a minimally invasive alternative capable of capturing tumor-derived epigenomic alterations and has consistently shown strong clinical utility in adult malignancies. However, genome-wide cfDNA methylation patterns across diverse pediatric and AYA sarcoma subtypes remain poorly defined. Methods: Plasma was collected from 93 pediatric and AYA patients (pediatric &lt;18 years; AYA 15-39 years) representing 27 Ewing sarcoma, 17 rhabdomyosarcoma, 11 liposarcoma, 10 chordoma, 8 synovial sarcoma, 7 chondrosarcoma, 6 osteosarcoma, and 6 fibrosarcoma cases, plus 19 matched healthy donors. cfDNA was isolated from 1 mL plasma, quantified by Qubit, and assessed by Bioanalyzer. Libraries were prepared using the NEBNext EM-seq v2 workflow with PCR cycles scaled to cfDNA input amount. Genome-wide sequencing (15× target depth) was followed by alignment, deduplication, and methylation calling. MultiQC was used to assess depth, duplication rate, conversion efficiency, and CpG coverage. Global methylation summaries were computed, and methylKit was used to generate per-CpG and 1-kb tiling matrices and initiate differential methylation analyses. Results: Ewing sarcoma patients had significantly higher plasma cfDNA concentrations than age- and sex-matched healthy donors (24.4 vs 4.6 ng/mL, p &lt; 0.0001), whereas cfDNA levels for other sarcoma subtypes overlapped with the healthy cohort. Low or undetectable cfDNA concentrations by Qubit were far more common among non-Ewing sarcoma samples (23 of 66) than Ewing sarcoma (1 of 27). All samples achieved sufficient CpG coverage for genome-wide methylation modeling. Global methylation summaries revealed no significant differences in mean β-values across sarcoma subtypes or versus healthy donors. An independent analysis of the Ewing subset identified 299 significant differentially methylated regions (DMRs), supporting the detectability of disease-specific methylation changes. Conclusions: These results demonstrate the feasibility of high-quality cfDNA methylome profiling across a large and diverse pediatric and AYA sarcoma cohort, including in plasma samples with cfDNA concentrations below the limit of detection. While global methylation levels appear broadly similar across subtypes, proof-of-concept DMR analysis in Ewing sarcoma suggests that subtype-specific epigenomic signatures could enable future noninvasive diagnostic tools for pediatric and AYA sarcomas. Citation Format: Lilli J. Greiner, Roman O. Kowalchuk, Jeff Szymanski, Pradeep S. Chauhan, Adam Amundson, Peter J. Schoettler, Wendy Allen-Rhoades, Stephanie F. Polites, Peter S. Rose, Kelly Bailey, Linda McAllister-Lucas, Anita Mahajan, Nadia Laack, Aadel Chaudhuri. Defining genome-wide cfDNA methylation landscapes in pediatric and adolescent and young adult (AYA) bone and soft-tissue sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7885.

Abstract Introduction: Detectable circulating tumor DNA (ctDNA) is associated with inferior outcomes in Ewing sarcoma (ES); however, ctDNA clears in nearly all patients within 2 of the 6 chemotherapy cycles before radiotherapy (RT) or surgery. Given a 3-year EFS of 37% on AEWS 1221 (metastatic) and 5-year EFS of 78% on AEWS 1031 (localized), current ctDNA testing fails to predict most relapses. Extracellular vesicles (EVs) are microscopic particles studied as a biomarker in multiple cancer types. We hope to improve the sensitivity of ctDNA in ES and provide the first application of EVs in ES. Methods: cfDNA was isolated from 1mL plasma, quantified by Qubit, and sequenced as NEBNext Enzymatic Methyl-seq v2 libraries. We performed a systematic unsupervised clustering analysis of 27 ES plasma cfDNA profiles using 4 differentially methylated regions (DMR) subsets (63 strong DMRs, top 30, top 15, and 10 promoter-proximal loci), 3 clustering algorithms (k-means, Ward hierarchical, PAM), and k=2-5 clusters, testing associations with tumor burden and progression. EV analysis involved antibody detection against ES surface markers, including LINGO1, ENPP1, CDH11, and CD99. Concentrations of EVs were determined by standardized and calibrated high-resolution flow cytometry then analyzed with custom-built software to automatically determine and apply gates. Samples were de-identified, randomly coded, and run in triplicates. The senior research technologist responsible for EV analysis was blinded to patient information and clinical data. Results: EV analysis included 36 pre-RT samples from 16 metastatic and 20 localized ES patients from a prospectively maintained biobank, with 27 pre-RT samples in the cfDNA analysis and 19 healthy donor (HD) samples. 35 of 36 patients had chemotherapy before sample collection. cfDNA concentrations were markedly elevated in ES patients compared with HD (24.4 vs 4.6 ng/mL, p&lt;0.0001), and 74% of ES samples exceeded the HD 95th-percentile detectability threshold (7.0 ng/mL). Across clustering configurations, ES cfDNA profiles consistently exhibited reproducible methylation substructure. One configuration (PAM clustering, k = 5, 63 strong DMRs) showed a modest but permutation-supported association with primary tumor size (nominal p ≈ 0.04; empirical p ≈ 0.03-0.04). ES samples had increased EV concentration compared to HD (p&lt;0.001), with AUC 0.988 for distinguishing between ES and HD ENPP1 (p&lt;0.0001). The highest ENPP1 EV values were in patients with large primary tumors (&gt;8 cm vs. ≤ 8cm) and metastatic disease (p=0.066). Conclusions: cfDNA- and EV-based liquid biopsy provide encouraging signals for high ES detectability pre-RT. We also show the first study of EVs as a novel biomarker in ES, which may provide complementary information to ctDNA. Multimodal liquid biopsy in ES may identify candidate patients for systemic or local therapy escalation and facilitate personalized care. Citation Format: Roman O. Kowalchuk, Lilli J. Greiner, Yohan Kim, Rubia Noori, Jeffrey Szymanski, William S. Harmsen, Pradeep S. Chauhan, Adam C. Amundson, Andrea M. McMahon, Peter J. Schoettler, Wendy A. Allen-Rhoades, Stephanie F. Polites, Peter S. Rose, Kelly M. Bailey, Linda M. McAllister-Lucas, Anita Mahajan, Fabrice Lucien-Matteoni, Nadia N. Laack, Aadel A. Chaudhuri. Multimodal liquid biopsy of Ewing sarcoma reveals high sensitivity prior to radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1149.

OBJECTIVE Brain metastases significantly impact neurocognitive function and overall survival. Stereotactic radiosurgery (SRS) is a cornerstone of treatment for patients with limited metastases and expected survival beyond 3 months. Despite current guidelines, up to 20% of patients with brain metastases undergoing SRS have been reported to die within 90 days. This study retrospectively evaluated prognostic factors associated with 90-day survival after SRS, aiming to improve patient selection. METHODS The authors retrospectively analyzed a cohort of 1546 patients who underwent Gamma Knife SRS for brain metastases at their institution between 2015 and 2023. One hundred seventy patients who survived less than 90 days after SRS were identified and case matched to 170 patients who survived over 90 days. Measured variables included patient demographic characteristics, tumor characteristics, treatment history, functional status, and control of the primary cancer. The authors modeled post-SRS 90-day survival using binomial and multivariate logistic regression. RESULTS Multivariate analysis highlighted Karnofsky Performance Score (KPS) < 70 (OR 17.4, p < 0.001), prior whole-brain radiation (OR 6, p = 0.004), and focal neurological deficits (OR 3.02, p = 0.003) as significant predictors of poor survival, whereas CNS progression before SRS (OR 0.22, p < 0.001) and control of systemic cancer (OR 0.556, p = 0.002) were associated with survival < 90 days. The predictive model demonstrated acceptable performance with an area under the curve (AUC) of 0.85, accuracy of 80%, sensitivity of 87%, and specificity of 71%. CONCLUSIONS Key predictors of 90-day survival after SRS for brain metastases include functional status (KPS), control of systemic cancer, CNS progression status, and focal neurological deficits. These findings are complementary factors that can assist in making decisions and SRS patient selection.

Abstract Background Children’s Oncology Group ACNS0333 treated atypical teratoid/rhabdoid tumor (ATRT) with surgery, chemotherapy (induction and consolidation) and radiation therapy (RT). M0 had focal RT and M+ had physician-selected focal RT or craniospinal (CSI). Methods Forty patients (29 M0, 11 M+) received RT. Pre-RT chemotherapy response was complete, partial, or stable disease. RT timing (age/stage-based) was pre-consolidation (RT-first) or post-consolidation (consolidation-first). Event-free survival (RT-EFS), overall survival (RT-OS), and cumulative incidence of local relapse (CILR) or distant relapse (RT-CIDR) were calculated. Analyses included log-rank tests and relative hazard rates with 95% confidence intervals to estimate proportional hazards regression. Results Four-year RT-EFS was 56.8% and 4-year RT-OS was 58.8% focal RT: 34 patients, CSI: 6 patients). A trend for superior RT-EFS for M+ compared to M0 (P = .0625, RHR 0.26; 95% CI 0.06-1.18) was shown. RT-EFS was improved for consolidation-first compared to RT-first timing (P = .037, RHR 0.43; 95% CI 0.13-1.37). Pre-RT chemotherapy response was associated with improved RT-EFS (P = .031) and RT-OS (P = .0069). Four-year RT-CILR was 7.84%; no differences in RT-CILR were shown for higher primary RT dose (≥5400 cGy, P = .38) or gross total resection (P = .80). 4-year RT-CIDR was 27.8% for M0 and 9.1% for M+ patients (P = .22). M+ had CSI (n = 6) or focal RT (n = 5). Fatal necrosis potentially-attributable to RT occurred in 3 RT-first patients (occuring either 1.6, 4.6, or 16.2 months post-treatment). Conclusions RT with intensive systemic therapy showed promising survival outcomes and effective primary disease control in ATRT. Sequencing RT prior to myeloblative chemotherapy, rather than post-consolidation, may be associated with increased risk of fatal radionecrosis.

ABSTRACT Background Proton beam therapy (PBT) offers dosimetric advantages in pediatric radiotherapy by reducing radiation exposure to healthy tissues. However, broad implementation raises important ethical, logistical, and equity considerations, especially in settings with limited access to advanced technologies. Procedure This position paper by the Paediatric Radiation Oncology Society (PROS) reviews the clinical rationale for selecting radiotherapy modalities in children, with a specific focus on ethical utilization of PBT. The document synthesizes evidence on the benefits and limitations of modern photon and proton therapies, explores disparities in access, outlines the role of local pediatric radiation oncologists, and addresses the impact of industry‐driven messaging on family decision‐making. Results While PBT offers clinical benefit in selecting pediatric cancers, high‐quality photon‐based treatments such as IMRT and VMAT remain effective and widely accessible alternatives. The referral and evaluation process for PBT is complex and may introduce treatment delays. Travel and financial burdens can exacerbate disparities. PROS underscores the critical role of local pediatric radiation oncologists in counseling families, and calls for balanced, evidence‐based communication from providers and industry stakeholders. Conclusions PROS advocates for an ethical, equitable, and evidence‐informed approach to radiotherapy modality selection in children, reflecting holistic considerations beyond dosimetry. Proton therapy should be pursued when clinically indicated and accessible without compromising timely care. Investment in a comprehensive radiation therapy infrastructure, including professional education, collaborative research, and responsible public messaging, is essential to optimize pediatric cancer outcomes globally.

Abstract Brain metastases significantly impact neurocognitive function and overall survival. Stereotactic radiosurgery (SRS) is a cornerstone of treatment for patients with limited metastases and expected survival beyond three months. Despite current guidelines, up to 20% of patients with brain metastases undergoing SRS have been reported to die within 90 days. This study retrospectively evaluates prognostic factors associated with 90-day survival after SRS, aiming to improve patient selection. We retrospectively analyzed a cohort of 1,546 patients who underwent Gamma Knife SRS for brain metastases at our institution between 2015 and 2023. One hundred seventy patients who survived fewer than 90 days post-SRS were identified and case-matched to 170 patients who survived over 90 days. Measured variables included patient demographics, tumor characteristics, treatment history, functional status, and control of the primary cancer. We modeled post-SRS 90-day survival using binomial and multivariate logistic regression. Multivariate analysis highlighted Karnofsky Performance Status (KPS) &lt; 70 (OR: 17.4, p &lt; 0.001), prior whole brain radiation (OR: 6, p = 0.004), and focal neurological deficits (OR: 3.02, p = 0.003) as significant predictors of early deaths, while CNS progression before SRS (OR: 0.22, p &lt; 0.001) and control of systemic cancer (OR: 0.556, p = 0.002) were associated with a less than 90-day survival. The predictive model demonstrated acceptable performance with an area under the curve (AUC) of 0.85, accuracy of 80%, sensitivity of 87%, and specificity of 71%. Key predictors of 90-day survival following SRS for brain metastases include functional status (KPS), control of systemic cancer, CNS progression status, and focal neurologic deficits. These findings are complementary factors that can assist in making decisions and SRS patient selection.