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Background Gliomas comprise the most common type of primary brain tumor, are highly invasive, and often fatal. IDH-mutated gliomas are particularly challenging to image and there is currently no clinically accepted method for identifying the extent of tumor burden in these neoplasms. This uncertainty poses a challenge to clinicians who must balance the need to treat the tumor while sparing healthy brain from iatrogenic damage. The purpose of this study was to investigate the feasibility of using resting-state blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to detect glioma-related asynchrony in vascular dynamics for distinguishing tumor from healthy brain. Methods Twenty-four stereotactically localized biopsies were obtained during open surgical resection from ten treatment-naïve patients with IDH-mutated gliomas who received standard-of-care preoperative imaging as well as echo-planar resting-state BOLD fMRI. Signal intensity for BOLD asynchrony and standard-of-care imaging was compared to cell counts of total cellularity (H&E), tumor density (IDH1 & Sox2), cellular proliferation (Ki67), and neuronal density (NeuN), for each corresponding sample. Results BOLD asynchrony was directly related to total cellularity (H&E, P = 4 × 10–5), tumor density (IDH1, P = 4 × 10–5; Sox2, P = 3 × 10–5), cellular proliferation (Ki67, P = .002), and inversely related to neuronal density (NeuN, P = 1 × 10–4). Conclusions Asynchrony in vascular dynamics, as measured by resting-state BOLD fMRI, correlates with tumor burden and provides a radiographic delineation of tumor boundaries in IDH-mutated gliomas.

BACKGROUND AND PURPOSE: Malignant glioma is a highly infiltrative malignancy that causes variable disruptions to the structure and function of the cerebrovasculature. While many of these structural disruptions have known correlative histopathologic alterations, the mechanisms underlying vascular dysfunction identified by resting-state blood oxygen level–dependent imaging are not yet known. The purpose of this study was to characterize the alterations that correlate with a blood oxygen level–dependent biomarker of vascular dysregulation. Materials and Methods: Thirty-two stereotactically localized biopsies were obtained from contrast-enhancing ( n = 16) and nonenhancing ( n = 16) regions during open surgical resection of malignant glioma in 17 patients. Preoperative resting-state blood oxygen level–dependent fMRI was used to evaluate the relationships between radiographic and histopathologic characteristics. Signal intensity for a blood oxygen level–dependent biomarker was compared with scores of tumor infiltration and microvascular proliferation as well as total cell and neuronal density. Results: Biopsies corresponded to a range of blood oxygen level–dependent signals, ranging from relatively normal ( z = −4.79) to markedly abnormal ( z = 8.84). Total cell density was directly related to blood oxygen level–dependent signal abnormality ( P = .013, R 2 = 0.19), while the neuronal labeling index was inversely related to blood oxygen level–dependent signal abnormality ( P = .016, R 2 = 0.21). The blood oxygen level–dependent signal abnormality was also related to tumor infiltration ( P = .014) and microvascular proliferation ( P = .045). Conclusions: The relationship between local, neoplastic characteristics and a blood oxygen level–dependent biomarker of vascular function suggests that local effects of glioma cell infiltration contribute to vascular dysregulation.

Objective Subependymomas are infrequent, low-grade gliomas associated with the ventricular system and the spinal cord. Little is known about the origin and natural history of these slow-growing lesions. Methods We identified all patients with pathologically proven subependymomas presenting to our institution between 1998 and 2016. We retrospectively reviewed clinical, radiographic, histologic, and surgical outcomes data in all patients who underwent surgical resection. Immunohistochemical analyses for cell lineage markers were performed. Results A total of 31 patients with pathologically proven subependymomas were identified. Of these, 7 asymptomatic lesions were discovered at autopsy and 24 symptomatic cases were treated surgically. There were 15 (48%) lateral ventricle tumors, 11 (35%) fourth ventricular tumors, and 5 (17%) spinal tumors. Symptomatic intracranial lesions most commonly presented with headaches and balance and gait abnormalities. Subependymomas had no distinguishing radiographic features that provided definitive preoperative diagnosis. At last follow-up, no patient treated surgically experienced recurrence. Immunohistochemical analyses demonstrated a diffusely GFAP-positive glial neoplasm with mixed populations of cells that were variably positive for Olig2, NHERF1, Sox2, and CD44. The Ki67 proliferation index was generally low ( Conclusions Subependymomas demonstrate mixed populations of cells expressing glial lineage markers as well as putative stem cell markers, suggesting these tumors may arise from multipotent glial progenitors that reside in the subventricular zone. Definitive diagnosis requires surgical sampling. Although the clinical course of subependymomas appears benign, the inability to radiographically diagnose these lesions, and the possibility of an alternative malignant lesion support a low threshold for early and safe maximal resection.

OBJECTIVEExtent of resection is an important prognostic factor in patients undergoing surgery for glioblastoma (GBM). Recent evidence suggests that intravenously administered fluorescein sodium associates with tumor tissue, facilitating safe maximal resection of GBM. In this study, the authors evaluate the safety and utility of intraoperative fluorescein guidance for the prediction of histopathological alteration both in the contrast-enhancing (CE) regions, where this relationship has been established, and into the non-CE (NCE), diffusely infiltrated margins.METHODSThirty-two patients received fluorescein sodium (3 mg/kg) intravenously prior to resection. Fluorescence was intraoperatively visualized using a Zeiss Pentero surgical microscope equipped with a YELLOW 560 filter. Stereotactically localized biopsy specimens were acquired from CE and NCE regions based on preoperative MRI in conjunction with neuronavigation. The fluorescence intensity of these specimens was subjectively classified in real time with subsequent quantitative image analysis, histopathological evaluation of localized biopsy specimens, and radiological volumetric assessment of the extent of resection.RESULTSBright fluorescence was observed in all GBMs and localized to the CE regions and portions of the NCE margins of the tumors, thus serving as a visual guide during resection. Gross-total resection (GTR) was achieved in 84% of the patients with an average resected volume of 95%, and this rate was higher among patients for whom GTR was the surgical goal (GTR achieved in 93.1% of patients, average resected volume of 99.7%). Intraoperative fluorescein staining correlated with histopathological alteration in both CE and NCE regions, with positive predictive values by subjective fluorescence evaluation greater than 96% in NCE regions.CONCLUSIONSIntraoperative administration of fluorescein provides an easily visualized marker for glioma pathology in both CE and NCE regions of GBM. These findings support the use of fluorescein as a microsurgical adjunct for guiding GBM resection to facilitate safe maximal removal.

BACKGROUND Accurate tissue sampling in nonenhancing (NE) gliomas is a unique surgical challenge due to their intratumoral histological heterogeneity and absence of contrast enhancement as a guide for intraoperative stereotactic guidance. Instead, T2/fluid-attenuated inversion-recovery (FLAIR) hyperintensity on MRI is commonly used as an imaging surrogate for pathological tissue, but sampling from this region can yield nondiagnostic or underdiagnostic brain tissue. Sodium fluorescein is an intraoperative fluorescent dye that has a high predictive value for tumor identification in areas of contrast enhancement and NE in glioblastomas. However, the underlying histopathological alterations in fluorescent regions of NE gliomas remain undefined. OBJECTIVE To evaluate whether fluorescein can identify diagnostic tissue and differentiate regions with higher malignant potential during surgery for NE gliomas, thus improving sampling accuracy. METHODS Thirteen patients who presented with NE, T2/FLAIR hyperintense lesions suspicious for glioma received fluorescein (10%, 3 mg/kg intravenously) during surgical resection. RESULTS Patchy fluorescence was identified within the T2/FLAIR hyperintense area in 10 of 13 (77%) patients. Samples taken from fluorescent regions were more likely to demonstrate diagnostic glioma tissue and cytologic atypia (P < .05). Fluorescein demonstrated a 95% positive predictive value for the presence of diagnostic tissue. Samples from areas of fluorescence also demonstrated greater total cell density and higher Ki-67 labeling than nonfluorescent biopsies (P < .05). CONCLUSION Fluorescence in NE gliomas is highly predictive of diagnostic tumor tissue and regions of higher cell density and proliferative activity.

Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where

BACKGROUND AND PURPOSE: The complex MR imaging appearance of glioblastoma is a function of underlying histopathologic heterogeneity. A better understanding of these correlations, particularly the influence of infiltrating glioma cells and vasogenic edema on T2 and diffusivity signal in nonenhancing areas, has important implications in the management of these patients. With localized biopsies, the objective of this study was to generate a model capable of predicting cellularity at each voxel within an entire tumor volume as a function of signal intensity, thus providing a means of quantifying tumor infiltration into surrounding brain tissue. MATERIALS AND METHODS: Ninety-one localized biopsies were obtained from 36 patients with glioblastoma. Signal intensities corresponding to these samples were derived from T1-postcontrast subtraction, T2-FLAIR, and ADC sequences by using an automated coregistration algorithm. Cell density was calculated for each specimen by using an automated cell-counting algorithm. Signal intensity was plotted against cell density for each MR image. RESULTS: T2-FLAIR ( r = −0.61) and ADC ( r = −0.63) sequences were inversely correlated with cell density. T1-postcontrast ( r = 0.69) subtraction was directly correlated with cell density. Combining these relationships yielded a multiparametric model with improved correlation ( r = 0.74), suggesting that each sequence offers different and complementary information. CONCLUSIONS: Using localized biopsies, we have generated a model that illustrates a quantitative and significant relationship between MR signal and cell density. Projecting this relationship over the entire tumor volume allows mapping of the intratumoral heterogeneity in both the contrast-enhancing tumor core and nonenhancing margins of glioblastoma and may be used to guide extended surgical resection, localized biopsies, and radiation field mapping.

In the version of this article originally published, the graph in Extended Data Fig. 2c was a duplication of Extended Data Fig. 2b. The correct version of Extended Data Fig. 2c is now available online.

BACKGROUND: The primary treatment of GBM is surgical resection of the contrast enhancing mass, while regions of non-enhancing tumor are left behind, and inevitably gives rise to recurrence. Thus, there is therapeutic significance to understanding the cellular and molecular features of the non-enhancing margins of GBM. Advances in comparative genetic and molecular analyses have uncovered patterns of gene expression and genetic alterations in GBM, and led to the recognition of clinically significant tumor subtypes. However, most previous studies have been based on analysis of tissue that was removed during surgery without documenting the radiographic location. This has precluded the systematic study of intra-tumoral heterogeneity, and its correlation with radiographic regions. We propose a method of sequential image guided biopsies, allowing for specimen localization, intra-tumoral comparative analysis, and the systematic study of infiltrated tissue beyond the borders of contrast enhancement. METHODS: In 77 patients with GBM, multiple stereotactic-guided biopsies were obtained from radiographically distinct regions prior to resection. The radiographic localization of each biopsy was mapped using the 3D intraoperative neuro-navigation system (BrainLab). Sampled regions included areas of contrast enhancement (CE) and adjacent non-enhancing FLAIR+ (NEF+). Samples from each region were divided into pieces processed for RNA-seq and histological analyses. RESULTS: There were significant differences in the cellular density and cellular composition between the CE and NEF+ samples. The CE samples had higher cellularity than NEF+ samples, and were more likely to contain the histological hallmarks of GBM, including vascular proliferation and pseudopalisading necrosis. In contrast, the NEF+ regions showed the histological features of diffusely infiltrating glioma with neoplastic glial cells intermingled with non-neoplastic and reactive cells. RNA-seq showed that the CE and NEF+ regions also had markedly different expression patterns. Comparisons between our image guided biopsies and the TCGA data set showed that the CE regions were enriched for genes associated with the mesenchymal, classical and proneural subtypes while the NEF+ region were enriched for genes of the neural subtype. Further analysis revealed that region-specific and subtype-specific differences in expression patterns were predominantly due to differences in the cellular composition. CONCLUSIONS: Cellular composition is a major determinant of the expression patterns seen at the non-enhancing margins of GBM. The different GBM subtypes show distinct expression patterns that relate the contrast enhancing centers to the non-enhancing margins of the tumors. Understanding these patterns provides a means to infer the molecular and cellular features of glioma tissue left behind after surgery. SECONDARY CATEGORY: Tumor Biology.