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Solid stress, distinct from fluid pressure, is a physical force contained in and transmitted by solid components of the brain tumor, including cells and the matrix they produce. Solid stress has been shown to promote tumor progression, and decrease anticancer therapy efficacy. This is especially relevant in brain tumors, as the rigid skull results in these trapped forces, increasing intracranial pressure, and potentially leading to other complications, including neuronal cell death. Here we present a novel method of quantifying these physical stresses in situ in both mice (glioblastoma [U87], brain metastasis [BT474], and ependymoma models) and patients. Briefly, following a craniotomy, mechanical forces that include solid stress are released, which causes the tissue to deform in peaks (areas under compression) and valleys (areas originally under tension). This tissue deformation is imaged via high-resolution ultrasound and analysed via custom MATLAB code to produce an accurate 3D model of the entire mouse brain, including the tumour region. For human samples, a pre-operative MRI is used to generate a detailed 3D model of the human brain. During surgery, the trapped physical stresses results in a bulge of the dura post craniotomy. We use BrainLab to measure the craniotomy induced brain deformation, which is then registered to the pre-operation MRI before being analysed in an identical fashion to the murine models using SolidWorks and Abaqus. We further show that in the brain metastases model, chemotherapy reduces compression stresses by 51%. Further, our technique results in fast processing time (~ 15 minutes), and has the potential to prevent the need for intraoperative MRI based on position simulations. As such, solid stress measurements provide a new class of mechanical biomarkers that can be correlated to clinical outcomes for predictive and prognostic value.

Purpose Although maximal resection of wild-type GBM tumors is associated with longer survival, the association of genomic alterations with the ability to resect disease has not been elucidated. This study aimed to determine whether certain molecular alterations are less amenable to surgical resection and whether achieving a surgical margin devoid of tumor cell burden provides a clinical benefit. Methods Molecular profiling of 148 consecutive tumor samples from newly diagnosed patients with IDH-WT GBM SNaPshot genotyping, and methylation-specific PCR for MGMT promoter methylation. The association of alterations with residual volume and progression-free survival was evaluated in regression analyses. We prospectively investigated the impact of TERTp status at the surgical margin on progression-free survival (PFS) in 47 patients. PFS and overall survival (OS) were evaluated with the log-rank test and Cox regression models.Results Overall, 148 patients (91 men [61.5%], median age, 62.5 years [range 56–70 years] had maximally safe surgery. The median follow-up duration was 18 months (IQR, 4-32 months). The rate of PFS was significantly lower in MGMT promoter unmethylated IDH-WT GBM amenable to resection with residual volume >4.9cc (hazard ratio [HR], 2.35; 95% CI, 1.44-3.84; P=.005). Gene amplification (PDGFRA, KIT, KDR) on 4q12 and TP53 and RB1 mutations were associated with greater RV. Prospective trial revealed median PFS for tumors with TERTp mutations in the surgical margin was 10.1 months while tumors with undetectable TERTp mutations in the margin did not progress (median follow-up 8.1 months, IQR 1.6-14.6). Surgical tumor margins devoid of TERTp mutations were associated with significantly different probability of PFS (0.23; 95%CI 0.15-0.43; P< 0.01)Conclusion In conclusion, 4q12 amplification (KDR/PDGFRA/KIT) and tumor suppressor gene alterations (RB1, TP53) were associated with greater residual volume. Tumor-free margins defined spatially by intraoperative navigation as assessed by quantifying TERTp mutation allelic fraction was correlated with prolonged PFS.