Citations

Background: Proton beam irradiation to the ventricular myocardium may enable non-invasive targeting of ventricular tachycardia. Previous work has demonstrated the feasibility of imaging ablation lesion with late gadolinium enhanced (LGE) cardiac magnetic resonance imaging (MRI). Hypothesis: We hypothesize that proton beam irradiation will lead to progressively increasing density of LGE corresponding to lesion formation during follow-up after treatment delivery. Aim: The aim of the current study was to determine the time course of LGE intensity in ventricular myocardium following proton beam therapy. Methods: Eleven swine were irradiated with 40 Gy proton beam in the anterior or lateral left ventricular (LV) followed by LGE cardiac MRI every 4 weeks for up to 24 weeks. After manual contouring of the endocardial and epicardial myocardium, a region of interest (ROI) in the area irradiated with 0-5 Gy was contoured (remote ROI). The mean and standard deviation (SD) of the signal intensity (SI) of the remote ROI were calculated. Light LGE was defined as voxels with SI > mean+2SD but < mean+3SD of the remote ROI, while voxels with SI > mean+3SD of the remote ROI were classified as having dense LGE. Voxels identified as bright due to image artifacts or noise were manually removed. The analysis was conducted in a fashion blinded to swine ID and time point after irradiation. Results: A total of 33 time points were analyzed (3.1 ± 1.4 MRI studies per swine). Figure 1A shows a representative time course of LGE in the same swine, progressing from diffuse light LGE at 8 weeks to dense LGE at 16-24 weeks. Figure 1B demonstrates the proportion of light versus dense LGE across timepoints in irradiated myocardial regions. At 8 weeks, light and dense LGE areas were evenly distributed. At 12 to 24 weeks, dense LGE increased to approximately 75%. The proportion of dense versus light LGE was significantly higher at 12, 16, and 24 weeks, as compared to 8 weeks. Conclusion: In ventricular myocardium, diffuse light LGE evident at 8 weeks progresses to denser LGE at 12-24 weeks following proton beam irradiation corresponding with lesion formation.

Abstract Most TERT promoter (TERTp) clinically relevant sequence variants in CNS tumors are the canonical C228T and C250T mutations. Non-canonical TERTp mutations have been reported mainly in non-CNS tumors. We describe 12 CNS tumors with non-canonical TERTp variants interpreted as clinically relevant. Using clinical targeted NGS panels (2020-2024), we detected c.-100_-79dup (n=2), c.-92_-91insGGCGGCCCCGCCCCTTCCTTTC (n=1), c.-118_-117insTCCCCGGCCCAGCCCCTTCCGGG (n=1), c.-123_-76dup (n=1), c.-110_-89dup (n=2), and c.-57A&gt;C (n=5). Most cases had chromosomal microarray (n=11) and/or methylation array data analyzed using the NCI/Bethesda v.2 classifier (n=9). All non-canonical TERTp variants occurred at a variant allele frequency suggestive of somatic clonal origin (mean, 34%; range, 18-46), and in adults (mean age, 60 years; range, 36-88). Except for the c.-57A&gt;C variant, all non-canonical TERTp variants occurred in tumors with histological and/or molecular diagnostic features of glioblastoma, IDH-wildtype (GBM), often epigenetically aligning to this tumor type. All five tested cases matched to superfamily glioblastoma (score ≥ 0.9), with three to class GBM_RTK_I (&gt;0.9 in 2, 0.86 in 1) and two to GBM_RTK_II (&gt;0.9). The size and sequence of such variants suggest that these may be functionally equivalent to canonical mutations or generate favorable TERTp activation motif conformations like previously reported activating duplications. The c.-57A&gt;C variant is a well-established oncogenic mutation observed in other cancer types but has not been reported in CNS tumors. We describe five cases with the c.-57A&gt;C variant: one GBM matching to methylation class GBM_MES_TYP (0.99); two oligodendroglioma, IDH-mutant and 1p/19q-codeleted, one of which had methylation data matching to class O_IDH (0.99); one diffuse glioma, IDH-mutant, which was partially 1p/19q-codeleted and matched to class O_IDH (0.99); and one anaplastic meningioma, aligning to superfamily meningioma (0.99)/MNG_MAL (0.79). Our findings show that non-canonical TERTp variants typically occur in tumor types that often harbor TERTp canonical mutations, expanding the spectrum of TERTp clinically relevant variants that are molecular biomarkers in CNS tumors.

BACKGROUND AND OBJECTIVE: This investigation evaluates the safety and efficacy of stereotactic radiosurgery (SRS) vs observation for Koos grade I vestibular schwannomas (VS). METHODS: In a multicenter study, we retrospectively analyzed data of patients with Koos grade I VS who underwent SRS (SRS group) or were observed (observation group). Propensity score matching was used to equilibrate demographics, tumor size, and audiometric data across groups. The outcome analyzed included tumor control, preservation of serviceable hearing, and neurological function. RESULTS: The study matched 142 patients, providing a median follow-up period of 36 months. SRS significantly enhanced tumor control compared with observation, with a 100% control rate at both 5- and 8-year marks in the SRS group vs 48.6% and 29.5% in the observation group at the same time intervals, respectively ( P < .001). Preservation of serviceable hearing outcomes between groups showed no significant difference at 5 and 8 years, ensuring a comparable quality of auditory function (SRS 70.1% vs observation 53.4% at 5 years; P = .33). Furthermore, SRS was associated with a reduced likelihood of tinnitus (odds ratio [OR] = 0.46, P = .04), vestibular dysfunction (OR = 0.17, P = .002), and overall cranial nerve dysfunction (OR = 0.49, P = .03) at last follow-up. CONCLUSION: SRS management of patients with Koos grade I VS was associated with superior tumor control and reduced odds for cranial nerve dysfunction, while not compromising hearing preservation compared with observation. These findings support the safety and efficacy of SRS as a primary care approach for this patient population.

BACKGROUND AND OBJECTIVES: This study assessed the efficacy and safety of stereotactic radiosurgery (SRS) in comparison with watchful waiting for managing Koos grade II vestibular schwannomas (VS). METHODS: A retrospective, multicentric analysis was conducted, focusing on patients with Koos grade II VS who either received SRS (SRS group) or were observed (observation group). To ensure comparability between groups, propensity score matching was used, including factors such as demographic characteristics, tumor dimensions, and hearing assessments. The primary end points examined were tumor control, maintenance of serviceable hearing, and neurological outcomes. RESULTS: A total of 92 patients were equally matched across both cohorts, with a median follow-up of 37 months for the SRS group and 27.5 months for those observed. The SRS cohort exhibited superior tumor control over observation across 3, 5, and 8 years, achieving a 100% control rate vs 47.9%, 40.1%, and 34.3% for the observation group at these time intervals, respectively ( P < .001). Serviceable hearing preservation rates were comparable between the 2 groups throughout 3, 5, and 7 years (72.9% for SRS vs 65.4% for observation at 3 years; P = .86). Moreover, SRS management correlated with a lower incidence of vestibular symptoms (odds ratio = 0.11, P = .002), with no significant disparity in the deterioration of cranial nerve (CN) V or CN VII functions. Notably, the likelihood of experiencing any CN impairment was significantly diminished in the SRS cohort (odds ratio = 0.47, P = .04). CONCLUSION: For patients with Koos grade II VS, SRS offers superior tumor control rate and a lower risk of CN dysfunction without sacrificing hearing preservation.

Background Despite advances in cancer care and detection, >65% of patients with squamous cell cancer of the head and neck (HNSCC) will develop recurrent and/or metastatic disease. The prognosis for these patients is poor with a 5-year overall survival of 39%. Recent treatment advances in immunotherapy, including immune checkpoint inhibitors like pembrolizumab and nivolumab, have resulted in clinical benefit in a subset of patients. There is a critical clinical need to identify patients who benefit from these antiprogrammed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors. Methods Here, we report findings from a multicenter observational study, PREDicting immunotherapy efficacy from Analysis of Pre-treatment Tumor biopsies (PREDAPT), conducted across 17 US healthcare systems. PREDAPT aimed to validate OncoPrism-HNSCC, a clinical biomarker assay predictive of disease control in patients with recurrent or metastatic HNSCC treated with anti-PD-1 immune checkpoint inhibitors as a single agent (monotherapy) and in combination with chemotherapy (chemo-immunotherapy). The test used RNA-sequencing data and machine learning models to score each patient and place them into groups of low, medium, or high. Results The OncoPrism-HNSCC prediction significantly correlated with disease control in both the monotherapy cohort (n=62, p=0.004) and the chemo-immunotherapy cohort (n=50, p=0.01). OncoPrism-HNSCC also significantly predicted progression-free survival in both cohorts (p=0.015 and p=0.037, respectively). OncoPrism-HNSCC had more than threefold higher specificity than programmed death-ligand 1 combined positive score and nearly fourfold higher sensitivity than tumor mutational burden for predicting disease control. Conclusions Here, we demonstrate the clinical validity of the OncoPrism-HNSCC assay in identifying patients with disease control in response to anti-PD-1 immune checkpoint inhibitors. Trial registration number NCT04510129.