Background/Objectives: Locally recurrent osteosarcoma is associated with high patient morbidity and mortality, yet the risk factors for local recurrence remain incompletely understood. Therefore, the objective of this study was to comprehensively assess the impact of tumor histology, patient demographics, surgical resection, and chemotherapy delivery on the risk of local recurrence, development of metastases, and overall patient survival in osteosarcoma. Methods: This single-center retrospective review included 102 patients with skeletal osteosarcoma who underwent primary surgical resection between August 2001 and August 2021. Primary outcomes included the development and timing of local recurrence following primary resection. Data was abstracted from the electronic medical record, and statistical analyses were performed to identify demographic, tumor, or management (surgical and chemotherapy) related factors associated with an increased risk of local recurrence. Results: Locally recurrent osteosarcoma developed in 13.7% (n = 14) of patients after primary resection. Patients with local recurrence were more likely to have the chondroblastic subtype (57.1% versus 19.3% in those without local recurrence, p = 0.005). The chondroblastic subtype was associated with shorter local recurrence-free survival and overall survival than other histologic subtypes (p < 0.001). Resection approach, surgical margin status, histologically assessed response to neoadjuvant chemotherapy, and type and dose intensity of chemotherapy delivered were not statistically associated with risk of local recurrence. Conclusions: Chondroblastic histology is a risk factor for local recurrence in osteosarcoma and is associated with poor overall survival in our patient cohort.

High-grade gliomas (HGGs) and diffuse midline gliomas (DMGs) in pediatric patients carry a poor prognosis, necessitating the rapid development of novel therapies. Peptide vaccines represent a safe, repeatable, and rational immunotherapeutic modality aimed at inducing potent, tumor-specific T-cell responses. In this review, we define the scope of current progress by arguing that immunogenicity in children with HGG/DMG hinges on three factors: appropriate antigen class (neoantigen vs. TAA), the use of potent immunoadjuvants, and successful navigation of immune suppression. To address the gap between biological promise and clinical reality, we analyze clinical trials targeting shared tumor-associated antigens (e.g., CMV pp65, Survivin) and specific shared neoantigens (H3.3K27M). Crucially, we highlight pivotal data from the PNOC007 trial, where the magnitude of H3.3K27M-specific T-cell expansion correlated directly with significantly longer overall survival (OS), establishing a causal link between pharmacodynamics and clinical benefit. However, the unique challenges of the immunosuppressive tumor microenvironment and the detrimental effect of necessary corticosteroids remain paramount barriers. Future success relies on multi-modal combination strategies, the development of next-generation personalized neoantigen vaccines, and the application of advanced neuroimaging to accurately assess treatment response.