Faculty Bibliography

PURPOSE/UNASSIGNED:Glioblastoma (GBM) is the most common and aggressive primary adult brain tumor. The standard treatment approach is surgical resection to target the enhancing tumor mass, followed by adjuvant chemoradiotherapy. However, malignant cells often extend beyond the enhancing tumor boundaries and infiltrate the peritumoral edema. Traditional supervised machine learning techniques hold potential in predicting tumor infiltration extent but are hindered by the extensive resources needed to generate expertly delineated regions of interest (ROIs) for training models on tissue most and least likely to be infiltrated. APPROACH/UNASSIGNED:We developed a method combining expert knowledge and training-based data augmentation to automatically generate numerous training examples, enhancing the accuracy of our model for predicting tumor infiltration through predictive maps. Such maps can be used for targeted supra-total surgical resection and other therapies that might benefit from intensive yet well-targeted treatment of infiltrated tissue. We apply our method to preoperative multi-parametric magnetic resonance imaging (mpMRI) scans from a subset of 229 patients of a multi-institutional consortium (Radiomics Signatures for Precision Diagnostics) and test the model on subsequent scans with pathology-proven recurrence. RESULTS/UNASSIGNED:Leave-one-site-out cross-validation was used to train and evaluate the tumor infiltration prediction model using initial pre-surgical scans, comparing the generated prediction maps with follow-up mpMRI scans confirming recurrence through post-resection tissue analysis. Performance was measured by voxel-wised odds ratios (ORs) across six institutions: University of Pennsylvania (OR: 9.97), Ohio State University (OR: 14.03), Case Western Reserve University (OR: 8.13), New York University (OR: 16.43), Thomas Jefferson University (OR: 8.22), and Rio Hortega (OR: 19.48). CONCLUSIONS/UNASSIGNED:The proposed model demonstrates that mpMRI analysis using deep learning can predict infiltration in the peri-tumoral brain region for GBM patients without needing to train a model using expert ROI drawings. Results for each institution demonstrate the model's generalizability and reproducibility.

PURPOSE/OBJECTIVE:DNA methylation profiling stratifies isocitrate dehydrogenase (IDH)-mutant astrocytomas into methylation low-grade and high-grade groups. We investigated the utility of the T2-FLAIR mismatch sign for predicting DNA methylation grade and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion, a molecular biomarker for grade 4 IDH-mutant astrocytomas, according to the 2021 World Health Organization (WHO) classification. EXPERIMENTAL DESIGN/METHODS:Preoperative MRI scans of IDH-mutant astrocytomas subclassified by DNA methylation profiling (n=71) were independently evaluated by two radiologists for the T2-FLAIR mismatch sign. The diagnostic utility of T2-FLAIR mismatch in predicting methylation grade, CDKN2A/B status, copy number variation, and survival was analyzed. RESULTS:The T2-FLAIR mismatch sign was present in 21 of 45 (46.7%) methylation low-grade and 1 of 26 (3.9%) methylation high-grade cases (p<0.001), resulting in 96.2% specificity, 95.5% positive predictive value, and 51.0% negative predictive value for predicting low methylation grade. The T2-FLAIR mismatch sign was also significantly associated with intact CDKN2A/B status (p=0.028) with 87.5% specificity, 86.4% positive predictive value, and 42.9% negative predictive value. Overall multivariable Cox analysis showed that retained CDKN2A/B status remained significant for PFS (p=0.01). Multivariable Cox analysis of the histologic grade 3 subset, which was nearly evenly divided by CDKN2A/B status, CNV, and methylation grade, showed trends toward significance for DNA methylation grade with OS (p=0.045) and CDKN2A/B status with PFS (p=0.052). CONCLUSIONS:The T2-FLAIR mismatch sign is highly specific for low methylation grade and intact CDKN2A/B in IDH-mutant astrocytomas.

Although gliomatosis cerebri (GC) has been removed as an independent tumor type from the WHO classification, its extensive infiltrative pattern may harbor a unique biological behavior. However, the clinical implication of GC in the context of the 2021 WHO classification is yet to be unveiled. This study investigated the incidence, clinicopathologic and imaging correlations, and prognostic implications of GC in adult-type diffuse glioma patients. Retrospective chart and imaging review of 1,211 adult-type diffuse glioma patients from a single institution between 2005 and 2021 was performed. Among 1,211 adult-type diffuse glioma patients, there were 99 (8.2%) patients with GC. The proportion of molecular types significantly differed between patients with and without GC (P = 0.017); IDH-wildtype glioblastoma was more common (77.8% vs. 66.5%), while IDH-mutant astrocytoma (16.2% vs. 16.9%) and oligodendroglioma (6.1% vs. 16.5%) were less common in patients with GC than in those without GC. The presence of contrast enhancement, necrosis, cystic change, hemorrhage, and GC type 2 were independent risk factors for predicting IDH mutation status in GC patients. GC remained as an independent prognostic factor (HR = 1.25, P = 0.031) in IDH-wildtype glioblastoma patients on multivariable analysis, along with clinical, molecular, and surgical factors. Overall, our data suggests that although no longer included as a distinct pathological entity in the WHO classification, recognition of GC may be crucial considering its clinical significance. There is a relatively high incidence of GC in adult-type diffuse gliomas, with different proportion according to molecular types between patients with and without GC. Imaging may preoperatively predict the molecular type in GC patients and may assist clinical decision-making. The prognostic role of GC promotes its recognition in clinical settings.

BACKGROUND:Isocitrate dehydrogenase (IDH) mutant astrocytoma grading, until recently, has been entirely based on morphology. The 5th edition of the Central Nervous System World Health Organization (WHO) introduces CDKN2A/B homozygous deletion as a biomarker of grade 4. We sought to investigate the prognostic impact of DNA methylation-derived molecular biomarkers for IDH mutant astrocytoma. METHODS:We analyzed 98 IDH mutant astrocytomas diagnosed at NYU Langone Health between 2014 and 2022. We reviewed DNA methylation subclass, CDKN2A/B homozygous deletion, and ploidy and correlated molecular biomarkers with histological grade, progression free (PFS), and overall (OS) survival. Findings were confirmed using 2 independent validation cohorts. RESULTS:There was no significant difference in OS or PFS when stratified by histologic WHO grade alone, copy number complexity, or extent of resection. OS was significantly different when patients were stratified either by CDKN2A/B homozygous deletion or by DNA methylation subclass (P value = .0286 and .0016, respectively). None of the molecular biomarkers were associated with significantly better PFS, although DNA methylation classification showed a trend (P value = .0534). CONCLUSIONS:The current WHO recognized grading criteria for IDH mutant astrocytomas show limited prognostic value. Stratification based on DNA methylation shows superior prognostic value for OS.

The most widely used fluorophore in glioma-resection surgery, 5-aminolevulinic acid (5-ALA), is thought to cause the selective accumulation of fluorescent protoporphyrin IX (PpIX) in tumour cells. Here we show that the clinical detection of PpIX can be improved via a microscope that performs paired stimulated Raman histology and two-photon excitation fluorescence microscopy (TPEF). We validated the technique in fresh tumour specimens from 115 patients with high-grade gliomas across four medical institutions. We found a weak negative correlation between tissue cellularity and the fluorescence intensity of PpIX across all imaged specimens. Semi-supervised clustering of the TPEF images revealed five distinct patterns of PpIX fluorescence, and spatial transcriptomic analyses of the imaged tissue showed that myeloid cells predominate in areas where PpIX accumulates in the intracellular space. Further analysis of external spatially resolved metabolomics, transcriptomics and RNA-sequencing datasets from glioblastoma specimens confirmed that myeloid cells preferentially accumulate and metabolize PpIX. Our findings question 5-ALA-induced fluorescence in glioma cells and show how 5-ALA and TPEF imaging can provide a window into the immune microenvironment of gliomas.

Listeriosis has more than a 50% mortality when the central nervous system is involved, necessitating rapid diagnosis and treatment. We present four patients with brain abscesses in the setting of diagnosed neurolisteriosis, all of which demonstrated an odd presentation of multiple small, contiguous tubular lesions with rim enhancement on magnetic resonance imaging. Our review of published cases of neurolisteriosis suggests that this may be a useful pattern to identify neurolisteriosis abscesses, allowing earlier detection and therapy.

We describe 2 cases of a spinal cord lesion with imaging features closely resembling those described in supratentorial multinodular and vacuolating neuronal tumor (MVNT) or infratentorial multinodular and vacuolating posterior fossa lesions of unknown significance. Multiple well-delineated nonenhancing T2-hyperintense intramedullary cystic ovoid nodules were visualized within the white matter of the spinal cord, including some immediately abutting the gray matter. No alterations in signal intensity or morphology were detected in a follow-up. Moreover, no relevant clinical symptoms attributable to the lesions were present. We describe these lesions as presumed MVNT, and we therefore use the term MVNT-like spinal cord lesions.