Curry, William T.

Abstract Background To determine if dose escalation improves outcomes for chondrosarcomas (CHS) of the base of the skull (BOS) and the cervical spine (CS). Methods A prospective, randomized, dose-escalation trial was designed for patients with CHS of the BOS and CS. Patients were randomly assigned to 70 Gy (RBE) or 76 Gy (RBE). The primary endpoint was local failure (LF). Secondary endpoints included overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), and treatment-related toxicities. Results Between 1987 and 2007, 105 patients were randomized, median follow-up was 29.2 years (IQR, 26.7-32.4). Forty-six patients were assigned to 70 Gy (RBE) and 59 were assigned to 76 Gy (RBE). LF at 5-, 10-, and 20 years were 7%, 9%, and 11% for 70 Gy (RBE), and 10%, 15%, and 19% for 76 Gy (RBE) (P = .16). Like LF rates, there was no benefit in dose escalation for OS (P = .28) and CSS (P = .22). Progression-free survival at 5-, 10-, and 20 years was 93%, 89%, and 77% for the low-dose group and 83%, 71%, and 59% for the high-dose group (P = .069). Late RT injury ≥ grade 3 was reported in a total of 19 (18%) patients across both dose levels, with 11% in the low-dose group and 24% in the high-dose group (P = .13). Conclusions This is the first and largest trial of patients with grade I/II BOS and CS CHS evaluating dose escalation for tumor control. Proton-based RT is effective and safe for these tumors, but there is no apparent benefit in dose escalation. Clinical Trial Information NCT00592748.

Abstract High-grade gliomas (HGGs) are aggressive, infiltrative brain tumors with poor survival outcomes and limited therapeutic options. Their spatial and molecular heterogeneity necessitates large, well-curated datasets integrating imaging, clinical, and genomic information to enable precision medicine and drive novel treatment development. Using the Medtronic StealthStation neuronavigation system, we collected over 1,000 spatially localized intraoperative biopsy samples from more than 250 patients undergoing resection for glioma at Mayo Clinic and partnering sites. Each biopsy site was recorded with 3D coordinates, labeled in real time, flash-frozen, and annotated with metadata including collection time, anatomical location, and surgical plan. Samples were processed and entered into a secure database along with the corresponding sampling coordinates, frozen pathology, whole-exome and RNA sequencing data, 5-ALA fluorescence status, patient demographics, and T1, T1Gd, T2, and T2-FLAIR MRI. This multimodal dataset supports radiogenomic research by enabling precise mapping of imaging features to molecular characteristics. A subset of this data, including 268 biopsies from 52 patients (25 male, 27 female) with reported intraoperative 5-ALA fluorescence, was used to develop a radiomics model predicting locoregional patterns of 5-ALA positivity based on preoperative MRI. Image features were extracted from the biopsy sample coordinates across multiple MRI sequences and paired with corresponding 5-ALA fluorescence status to train the model for regional fluorescence prediction. The final model achieved 83% accuracy on the training set and 86% on the validation set using a 70-15-15 data split; this included 208 samples for training and 42 for validation, stratified by patient to ensure no overlap of samples from the same individual across sets. These findings demonstrate the feasibility of predicting 5-ALA fluorescence using radiomic features from standard preoperative MRI, offering a promising noninvasive strategy for improving intraoperative decision-making and enabling more precise, personalized resections in patients with high-grade gliomas.

Abstract BACKGROUND Craniopharyngiomas, primary brain tumors of the pituitary-hypothalamic axis, can cause significant clinical sequelae. Treatment using surgery, radiation, or both often entails significant morbidity. In prior work, we demonstrated that ninety-five percent of papillary craniopharyngiomas (PCP) harbor BRAF V600E mutations (Brastianos et al. Nature Genetics 2014). In this multicenter National Cancer Institute cooperative group trial (Alliance A071601), we evaluated the safety and efficacy of BRAF/MEK inhibition in patients with PCP without prior irradiation. METHODS Eligible patients, with measurable disease and whose PCP screened positively for BRAF mutations, without prior radiation, received the BRAF/MEK inhibitor combination vemurafenib/cobimetinib in 28-day cycles. The primary endpoint of objective response rate at 4 months based on centrally determined volumetric data was evaluated in 16 patients on this single arm phase 2 trial. RESULTS Based on volumetric response criteria by central radiology review, 15 of 16 patients (94%; 95% CI: 70% to 100%) had a durable objective partial response to therapy. Thus, this study met primary endpoint for overall response rate. The median tumor reduction was 91% (range of 68% to 99%). Median follow-up was 22 months (95% CI: 19 to 30 months) and median number of treatment cycles was 8. Median progression-free survival and duration of response were not yet reached. Three patients progressed during follow-up after therapy was discontinued; none have died. The sole non-responder stopped treatment after eight days due to toxicity. Grade 3 toxicities at least possibly related to treatment occurred in 12 patients (rash in 6 patients). Grade 4 toxicities were observed in two patients: hyperglycemia (n=1) and increased creatine phosphokinase (n=1). Three patients discontinued treatment for adverse events. CONCLUSIONS Our study indicates that BRAF/MEK inhibitors are a safe and effective treatment for PCP without prior irradiation. Support: U10CA180821, U10CA180882; U24CA196171, U10CA180868 (NRG); Genentech; . ClinicalTrials.gov Identifier: NCT03224767.