Faculty Bibliography

BACKGROUND:The incidence of leptomeningeal metastases (LM) has been reported diversely. This study aimed to investigate the incidence, risk factors, and prognosis of LM in patients with IDH-wildtype glioblastoma. METHODS:A total of 828 patients with IDH-wildtype glioblastoma were enrolled between 2005 and 2022. Baseline preoperative MRI including post-contrast fluid-attenuated inversion recovery (FLAIR) was used for LM diagnosis. Qualitative and quantitative features, including distance between tumor and subventricular zone (SVZ) and tumor volume by automatic segmentation of the lateral ventricles and tumor, were assessed. Logistic analysis of LM development was performed using clinical, molecular, and imaging data. Survival analysis was performed. RESULTS:The incidence of LM was 11.4%. MGMTp unmethylation (odds ratio [OR] = 1.92, P = 0.014), shorter distance between tumor and SVZ (OR = 0.94, P = 0.010), and larger contrast-enhancing tumor volume (OR = 1.02, P < 0.001) were significantly associated with LM. The overall survival (OS) was significantly shorter in patients with LM than in those without (log-rank test; P < 0.001), with median OS of 12.2 and 18.5 months, respectively. Presence of LM remained an independent prognostic factor for OS in IDH-wildtype glioblastoma (hazard ratio = 1.42, P = 0.011), along with other clinical, molecular, imaging, and surgical prognostic factors. CONCLUSION/CONCLUSIONS:The incidence of LM is high in patients with IDH-wildtype glioblastoma, and aggressive molecular and imaging factors are correlated with LM development. The prognostic significance of LM based on post-contrast FLAIR imaging suggests acknowledgement of post-contrast FLAIR as a reliable diagnostic tool for clinicians.

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.

Isocitrate dehydrogenase (IDH) mutation status has emerged as an important prognostic marker in gliomas. This study sought to develop deep learning networks for non-invasive IDH classification using T2w MR images while comparing their performance to a multi-contrast network. Methods: Multi-contrast brain tumor MRI and genomic data were obtained from The Cancer Imaging Archive (TCIA) and The Erasmus Glioma Database (EGD). Two separate 2D networks were developed using nnU-Net, a T2w-image-only network (T2-net) and a multi-contrast network (MC-net). Each network was separately trained using TCIA (227 subjects) or TCIA + EGD data (683 subjects combined). The networks were trained to classify IDH mutation status and implement single-label tumor segmentation simultaneously. The trained networks were tested on over 1100 held-out datasets including 360 cases from UT Southwestern Medical Center, 136 cases from New York University, 175 cases from the University of Wisconsin-Madison, 456 cases from EGD (for the TCIA-trained network), and 495 cases from the University of California, San Francisco public database. A receiver operating characteristic curve (ROC) was drawn to calculate the AUC value to determine classifier performance. Results: T2-net trained on TCIA and TCIA + EGD datasets achieved an overall accuracy of 85.4% and 87.6% with AUCs of 0.86 and 0.89, respectively. MC-net trained on TCIA and TCIA + EGD datasets achieved an overall accuracy of 91.0% and 92.8% with AUCs of 0.94 and 0.96, respectively. We developed reliable, high-performing deep learning algorithms for IDH classification using both a T2-image-only and a multi-contrast approach. The networks were tested on more than 1100 subjects from diverse databases, making this the largest study on image-based IDH classification to date.

UNLABELLED:Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE:The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.

BACKGROUND AND PURPOSE:Most multinodular and vacuolating neuronal tumors (MVNTs) are diagnosed and followed radiologically without any change across time. There are no surveillance guidelines or quantitative volumetric assessments of these tumors. We evaluated MVNT volumes during long follow-up periods using segmentation tools with the aim of quantitative assessment. MATERIALS AND METHODS:All patients with MVNTs in a brain MR imaging report in our system were reviewed. Patients with only 1 brain MR imaging or in whom MVNT was not clearly the most likely diagnosis were excluded. All MVNTs were manually segmented. For all follow-up examinations, absolute and percentage volume change from immediately prior and initial examinations were calculated. RESULTS:= .67), respectively. CONCLUSIONS:MVNT segmentation across follow-up brain MR imaging examinations did not demonstrate significant volume differences, suggesting that these tumors do not enlarge with time. Hence, frequent surveillance imaging of newly diagnosed MVNTs may not be necessary.

A 74-year-old man with chronic obstructive pulmonary disease, glaucoma, and Stage IIIB squamous cell lung cancer experienced several minutes of flashing lights in his right visual hemifield, followed by onset of a right visual field defect. On examination, the patient had a right homonymous hemianopsia that was most dense inferiorly by confrontation testing. Emergent CT scan of the head revealed a 2.5 × 3 cm hypodensity in the left occipital lobe, which was interpreted as an acute stroke. Continuous EEG monitoring captured left posterior quadrant seizures that were temporally correlated to the positive visual phenomena. Subsequent MRI of the brain with and without contrast revealed a conglomerate of centrally necrotic and peripherally enhancing mass lesions. On biopsy, a thick purulent material was drained and Gram stain of the sample revealed gram-positive beaded rods, which speciated to Nocardia farcinica. The patient was treated with a six-week course of intravenous meropenem and a one-year course of oral trimethroprim-sulfamethoxazole. On follow-up, the patient experienced resolution of the right visual field deficit.

PURPOSE/OBJECTIVE:While the T2-FLAIR mismatch sign is highly specific for isocitrate dehydrogenase (IDH)-mutant, 1p/19q-noncodeleted astrocytomas among lower-grade gliomas, its utility in WHO grade 4 gliomas is not well-studied. We derived the partial T2-FLAIR mismatch sign as an imaging biomarker for IDH mutation in WHO grade 4 gliomas. METHODS:Preoperative MRI scans of adult WHO grade 4 glioma patients (n = 2165) from the multi-institutional ReSPOND (Radiomics Signatures for PrecisiON Diagnostics) consortium were analyzed. Diagnostic performance of the partial T2-FLAIR mismatch sign was evaluated. Subset analyses were performed to assess associations of imaging markers with overall survival (OS). RESULTS:One hundred twenty-one (5.6%) of 2165 grade 4 gliomas were IDH-mutant. Partial T2-FLAIR mismatch was present in 40 (1.8%) cases, 32 of which were IDH-mutant, yielding 26.4% sensitivity, 99.6% specificity, 80.0% positive predictive value, and 95.8% negative predictive value. Multivariate logistic regression demonstrated IDH mutation was significantly associated with partial T2-FLAIR mismatch (odds ratio [OR] 5.715, 95% CI [1.896, 17.221], p = 0.002), younger age (OR 0.911 [0.895, 0.927], p < 0.001), tumor centered in frontal lobe (OR 3.842, [2.361, 6.251], p < 0.001), absence of multicentricity (OR 0.173, [0.049, 0.612], p = 0.007), and presence of cystic (OR 6.596, [3.023, 14.391], p < 0.001) or non-enhancing solid components (OR 6.069, [3.371, 10.928], p < 0.001). Multivariate Cox analysis demonstrated cystic components (p = 0.024) and non-enhancing solid components (p = 0.003) were associated with longer OS, while older age (p < 0.001), frontal lobe center (p = 0.008), multifocality (p < 0.001), and multicentricity (p < 0.001) were associated with shorter OS. CONCLUSION/CONCLUSIONS:Partial T2-FLAIR mismatch sign is highly specific for IDH mutation in WHO grade 4 gliomas.