Citations

Objective: Pediatric patients with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) undergo aggressive multimodality treatment. This single institutional analysis of outcomes in this group explored factors associated with local control and survival. Methods: Patients ≤18 years old diagnosed with NRSTS between 10/1990-11/2021 who received radiotherapy (RT) were retrospectively identified. Overall Survival (OS) and disease-free survival (DFS) analyses were performed using Kaplan Meier methods. Cumulative incidence of local and distant failure were estimated. Univariate analysis was performed. Results: Fifty-one pediatric patients with NRSTS were included. Extremity tumors were most common (33/51, 65%), with 80% T1 or T2 (AJCC 8 th ) and 90% non-metastatic. Surgery in 49/51 (96%) resulted in 32 (65%) R0 resections. All received RT (median EQD2 50 Gy, range 42.4-76.9), with brachytherapy or intraoperative (IORT) boosts in 21 cases (41%) (mean EQD2 24.5 Gy). 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 on univariate analysis. Two-year local failure incidence for EBRT was 18.1% and 5.3% for EBRT+boost (HR 3.67, p=0.24). Among 6 observed local failures, 5 occurred after EBRT alone, 3 of which had positive margins. Among the EBRT+boost group, 2 had positive margins, neither with local recurrence. Conclusion: Multimodality treatment of pediatric NRSTS results in 5-year OS and DFS around 70%. R0 resection is essential to optimize outcomes in this population. Although incidence of R1 resections has declined in the modern era, IORT/brachytherapy boost may have a role in selected patients at high-risk for local recurrence.

Apart from ancestry, personal or environmental covariates may contribute to differences in polygenic score (PGS) performance. We analyzed the effects of covariate stratification and interaction on body mass index (BMI) PGS (PGS BMI ) across four cohorts of European (N = 491,111) and African (N = 21,612) ancestry. Stratifying on binary covariates and quintiles for continuous covariates, 18/62 covariates had significant and replicable R 2 differences among strata. Covariates with the largest differences included age, sex, blood lipids, physical activity, and alcohol consumption, with R 2 being nearly double between best- and worst-performing quintiles for certain covariates. Twenty-eight covariates had significant PGS BMI –covariate interaction effects, modifying PGS BMI effects by nearly 20% per standard deviation change. We observed overlap between covariates that had significant R 2 differences among strata and interaction effects – across all covariates, their main effects on BMI were correlated with their maximum R 2 differences and interaction effects (0.56 and 0.58, respectively), suggesting high-PGS BMI individuals have highest R 2 and increase in PGS effect. Using quantile regression, we show the effect of PGS BMI increases as BMI itself increases, and that these differences in effects are directly related to differences in R 2 when stratifying by different covariates. Given significant and replicable evidence for context-specific PGS BMI performance and effects, we investigated ways to increase model performance taking into account nonlinear effects. Machine learning models (neural networks) increased relative model R 2 (mean 23%) across datasets. Finally, creating PGS BMI directly from GxAge genome-wide association studies effects increased relative R 2 by 7.8%. These results demonstrate that certain covariates, especially those most associated with BMI, significantly affect both PGS BMI performance and effects across diverse cohorts and ancestries, and we provide avenues to improve model performance that consider these effects.

ABSTRACTAccurate staging of nodal involvement in pediatric sarcoma patients is important to determine correct systemic and local therapy, with the goal to reduce subsequent recurrences. However, differences in lymph node staging strategies, definitions, and treatment protocols between the Children's Oncology Group (COG), European paediatric Soft tissue sarcoma Study Group (EpSSG), and the Cooperative Weichteilsarkom Studiengruppe (CWS) complicate comparisons. In this article, we aim to establish internationally recognized recommendations for lymph node assessment and treatment of children and adolescents diagnosed with rhabdomyosarcoma (RMS) and non‐rhabdomyosarcoma soft tissue sarcoma (NRSTS) according to the Consensus Conference Standard Operating Procedure methodology.

Abstract Inotuzumab ozogamicin (InO) is an antibody-calicheamicin conjugate with striking efficacy in B-cell acute lymphoblastic leukemia (B-ALL). However, there is wide interpatient variability in treatment response, and the genetic basis of this variation remains largely unknown. Using a genome-wide CRISPR screen, we discovered that the loss of DNA nucleotidylexotransferase (DNTT) is a primary driver of InO resistance. Mechanistically, the downregulation of DNTT attenuated InO–induced DNA damage response, cell cycle arrest, and mitochondrial apoptotic priming, thereby ultimately leading to leukemia resistance to InO. Ex vivo leukemia InO sensitivity was highly associated with DNTT expression in ALL blasts with substantial intraleukemia heterogeneity as revealed by single-cell RNA sequencing. Among patients with B-ALL enrolled in the Children's Oncology Group trial AALL1621, we observed consistent DNTT downregulation in residual blasts following InO treatment. The selection of DNTT-low blasts by InO therapy was also recapitulated in vivo using patient-derived xenograft models. Collectively, our data indicate that DNTT is a key regulator of calicheamicin response in leukemia and thus a potential biomarker for individualizing InO therapy in B-ALL.

Objectives: ImPACTS (Improving Acute Care Through Simulation) is a collaborative simulation-based program partnering pediatric specialty centers (“hubs”) with general emergency departments (GEDs) to improve pediatric acute care. Objective measurements of ImPACTS, such as evaluating Pediatric Readiness Score (PRS) and simulation-based outcome improvements, have been reported previously. Barriers to and facilitators of program involvement and the downstream effects of the program have not been previously described. This study explores these aspects and key drivers for successful collaboration. Methods: The authors performed open coding of semistructured interviews of hub team members and pediatric emergency care coordinators (PECCs) from community GED “spokes.” We then identified and explored themes within the categories of barriers to, facilitators of, and barrier mitigation strategies for successful partnerships from the perspectives of both groups. Results: Analysis generated 4 dominant themes: buy-in, communication, personnel, and logistics. Engagement, institutional support, and buy-in of site leaders and individual participants were crucial to successful implementation, without which the programs were not completed or never started. Hubs benefited from project involvement via increased local engagement in pediatric readiness, organizational support, and further buy-in from institutional leadership, allowing for the future continuation of ImPACTS and similar programs. Benefits experienced by GEDs impacted education, pediatric readiness, and clinical and financial partnerships across institutions. Additionally, spoke interviewees cited downstream effects of participation, including increased collaboration and improved relationships with hub sites as being the most impactful. Conclusion: Understanding the key drivers of all collaborators is instrumental in successfully implementing large-scale educational and quality initiatives like the ImPACTS program.

The NCCN Guidelines for Survivorship include recommendations for screening, evaluation, and treatment of psychosocial and physical problems resulting from adult-onset cancer and its treatment. They also include recommendations to promote healthy behaviors and immunizations in survivors and provide a framework for care coordination. These NCCN Guidelines Insights summarize the panel’s current recommendations regarding sexual health and fertility.

Background: The BeatAML Master Trial (BAMT) began in 2016 with a goal of determining the feasibility of a precision-medicine approach in treating acute myeloid leukemia (AML) in older adults ≥ 60 years of age where outcomes are poor. At the time, standard of care (SOC) for older patients with AML was intensive 7+3 chemotherapy (cytarabine + daunorubicin) if fit and hypomethylating agents (HMA: azacitidine or decitabine) if unfit. Besides confirming the feasibility, the early results (2019) from the Master Trial suggested that patients who received therapy on one of the sub-studies had a lower early death rate and superior overall survival compared to patients receiving off-protocol SOC, which was primarily single-agent HMA at the time. Since then, the 2019 approval of venetoclax (ven) + azacitidine for older unfit AML patients has been transformative and emerged as the SOC. Using data from the BAMT from 2016-2024, we suggest that knowing the comprehensive genomic profile of AML at the time of diagnosis is still beneficial in determining therapy that would lead to the optimal outcome and that development of targeted therapies and combination regimens with ven/HMA is still needed. Methods: This is a retrospective analysis of 1096 patients who consented and enrolled on the BAMT (NCT03013998) from Nov 2016 through Jun 2024. Patients ≥ 60 years with newly diagnosed AML were included. Patients underwent therapy on a BeatAML sub-study based on their genetics (N=433) or treatment off-protocol (N=663). We divided the patients according to what therapy they received: (1) Non-Intensive (Off-Protocol, N=121), (2) Ven/HMA (Off-Protocol, N=234), (3) Non-Intensive (Sub-Study, N=407), (4) Intensive (Sub-Study, N=26), and (5) Intensive (Off-Protocol, N=155). 94 patients received no treatment and 59 were unknown. Non-intensive therapies included primarily targeted agents or non-ven combinations. We analyzed baseline characteristics and demographics, overall survival (OS), and the impact of allogenic stem cell transplant (SCT). OS, using Kaplan-Meier method, was measured from the start of therapy to all-cause death, censoring patients at last follow-up. Results: Characteristics and demographics were similar between Groups 1, 2 and 3. Group 4 and 5 were treated with intensive chemotherapy and their characteristics are reflective of younger/fit patients appropriate for the intensive regimen. Groups 4 and 5 also had the longest median OS (mOS) of 40.2 months (95% CI: 13.9-not reached (NR)) and 42.3 months (95% CI: 25.1-NR) respectively. Group 3, which included patients treated with a non-intensive, targeted therapy on a sub-study, had an mOS of 14.0 months (95% CI: 12.3-16.7), which was similar to Group 2, treated with Ven/HMA, that had an mOS of 13.2 months (95% CI: 10.9-16.3). Lastly, patients in Group 1, who were treated primarily with HMA monotherapy, did poorly in comparison, with an mOS of 6.0 months (95% CI: 3.3-10.1). Additionally, we looked at the cumulative incidence rate (CIR) of SCT. The CIR in 12 months of Group 1 was 9.8% (95% CI: 6.9-13.4), Group 2: 5.4% (95% CI: 2.2-10.7), Group 3 and 4 combined: 35.0% (95% CI: 628.1-42.1), and Group 5: 13.1% (95% CI: 6.9-13.4). In a multi-variable analysis, after adjusting for typical favorable risk factors like NPM1 mutations and core binding factor, SCT was highly significant (p<0.0001) in improving OS with a hazard ratio of 0.23 (95% CI: 0.16-0.32), and Group 3 performed similarly to Group 2 (p=0.20). Conclusions: First, our results suggest that it is clinically relevant to correctly identify whether an intensive chemotherapy, targeted-therapy, or ven/HMA regimen is best suited for older AML patients, for which a precision-medicine trial is ideal for. Secondly, in this group of patients, our results show that patients treated with a non-intensive targeted therapy (Group 3) has a similar mOS to those treated with ven/HMA (Group 2). Especially after controlling for patient characteristics, patients in Group 2 performed similar to those in Group 3 (p=0.20). Patients in Group 3 were treated on Beat AML sub-studies which included targeted therapy alone or with non-venetoclax combinations, which is a strong rationale for continued development of targeted agents to optimize toxicity and quality of life with similar survival. Lastly, this data also supports the need to improve the ven/HMA SOC by developing combination regimens with targeted agents to further improve outcomes.