Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective.

Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.

Epigenetic Activation of WNT5A Drives Glioblastoma Stem Cell Differentiation and Invasive Growth.

Glioblastoma stem cells (GSCs) are implicated in tumor neovascularization, invasiveness, and therapeutic resistance. To illuminate mechanisms governing these hallmark features, we developed a de novo glioblastoma multiforme (GBM) model derived from immortalized human neural stem/progenitor cells (hNSCs) to enable precise system-level comparisons of pre-malignant and oncogene-induced malignant states of NSCs. Integrated transcriptomic and epigenomic analyses uncovered a PAX6/DLX5 transcriptional program driving WNT5A-mediated GSC differentiation into endothelial-like cells (GdECs). GdECs recruit existing endothelial cells to promote peritumoral satellite lesions, which serve as a niche supporting the growth of invasive glioma cells away from the primary tumor. Clinical data reveal higher WNT5A and GdECs expression in peritumoral and recurrent GBMs relative to matched intratumoral and primary GBMs, respectively, supporting WNT5A-mediated GSC differentiation and invasive growth in disease recurrence. Thus, the PAX6/DLX5-WNT5A axis governs the diffuse spread of glioma cells throughout the brain parenchyma, contributing to the lethality of GBM.

Quantitative Assessment of Preanalytic Variables on Clinical Evaluation of PI3/AKT/mTOR Signaling Activity in Diffuse Glioma.

Biomarker-driven therapeutic clinical trials require the implementation of standardized, evidence-based practices for sample collection. In diffuse glioma, phosphatidylinositol 3 (PI3)-kinase/AKT/mTOR (PI3/AKT/mTOR) signaling is an attractive therapeutic target for which window-of-opportunity clinical trials could facilitate the identification of promising new agents. Yet, the relevant preanalytic variables and optimal tumor sampling methods necessary to measure pathway activity are unknown. To address this, we used a murine model for isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) and human tumor tissue, including IDH-wildtype GBM and IDH-mutant diffuse glioma. First, we determined the impact of delayed time-to-formalin fixation, or cold ischemia time (CIT), on the quantitative assessment of cellular expression of 6 phosphoproteins that are readouts of PI3K/AK/mTOR activity (phosphorylated-proline-rich Akt substrate of 40 kDa (p-PRAS40, T246), -mechanistic target of rapamycin (p-mTOR; S2448); -AKT (p-AKT, S473); -ribosomal protein S6 (p-RPS6, S240/244 and S235/236), and -eukaryotic initiation factor 4E-binding protein 1 (p-4EBP1, T37/46). With CITs ≥ 2 hours, typical of routine clinical handling, all had reduced or altered expression with p-RPS6 (S240/244) exhibiting relatively greater stability. A similar pattern was observed using patient tumor samples from the operating room with p-4EBP1 more sensitive to delayed fixation than p-RPS6 (S240/244). Many clinical trials utilize unstained slides for biomarker evaluation. Thus, we evaluated the impact of slide storage conditions on the detection of p-RPS6 (S240/244), p-4EBP1, and p-AKT. After 5 months, storage at -80°C was required to preserve the expression of p-4EBP1 and p-AKT, whereas p-RPS6 (240/244) expression was not stable regardless of storage temperature. Biomarker heterogeneity impacts optimal tumor sampling. Quantification of p-RPS6 (240/244) expression in multiple regionally distinct human tumor samples from 8 patients revealed significant intratumoral heterogeneity. Thus, the accurate assessment of PI3K/AKT/mTOR signaling in diffuse glioma must overcome intratumoral heterogeneity and multiple preanalytic factors, including time-to-formalin fixation, slide storage conditions, and phosphoprotein of interest.

The detrimental effect of biopsy preceding resection in surgically accessible glioblastoma: results from the national cancer database.

PURPOSE: Aggressive resection in surgically-accessible glioblastoma (GBM) correlates with improved survival over less extensive resections. However, the clinical impact of performing a biopsy before definitive resection have not been previously evaluated. METHODS: We analyzed 17,334 GBM patients from the NCDB from 2010-2014. We categorized them into: "upfront resection" and "biopsy followed by resection". The outcomes of interes included OS, 30-day readmission/mortality, 90-day mortality, and length of hospital stay (LOS). The Kaplan-Meier methods and accelerated failure time (AFT) models were applied for survival analysis. Multivariable binary logistic regression were performed to compare differences among groups. Multiple imputation and propensity score matching (PSM) were conducted for validation. RESULTS: "Upfront resection" had superior OS over "biopsy followed by resection" (median OS:12.4 versus 11.1 months, log-rank p = 0.001). Similarly, multivariable AFT models favored "upfront resection" (time ratio[TR]:0.83, 95%CI: 0.75-0.93, p = 0.001). Patients undergoing "upfront gross-total resection (GTR)" had higher OS over "upfront subtotal resection (STR)", "GTR following STR", and "GTR or STR following initial biopsy" (14.4 vs. 10.3, 13.5, 13.3, and 9.1 months;TR: 1.00 [Ref.], 0.75, 0.82, 0.88, and 0.67). Recent years of diagnosis, higher income, facilities located in Southern regions, and treatment at academic facilities were significantly associated with the higher likelihood of undergoing upfront resection. Multivariable regression showed a decreased 30 and 90-day mortality for patients undergoing "upfront resection", 73% and 44%, respectively (p < 0.001). CONCLUSIONS: Pre-operative biopsies for surgically accessible GBM are associated with worse survival despite subsequent resection compared to patients undergoing upfront resection.

Functional alterations in cortical processing of speech in glioma-infiltrated cortex.

Recent developments in the biology of malignant gliomas have demonstrated that glioma cells interact with neurons through both paracrine signaling and electrochemical synapses. Glioma-neuron interactions consequently modulate the excitability of local neuronal circuits, and it is unclear the extent to which glioma-infiltrated cortex can meaningfully participate in neural computations. For example, gliomas may result in a local disorganization of activity that impedes the transient synchronization of neural oscillations. Alternatively, glioma-infiltrated cortex may retain the ability to engage in synchronized activity in a manner similar to normal-appearing cortex but exhibit other altered spatiotemporal patterns of activity with subsequent impact on cognitive processing. Here, we use subdural electrocorticography to sample both normal-appearing and glioma-infiltrated cortex during speech. We find that glioma-infiltrated cortex engages in synchronous activity during task performance in a manner similar to normal-appearing cortex but recruits a diffuse spatial network. On a temporal scale, we show that signals from glioma-infiltrated cortex have decreased entropy, which may affect its ability to encode information during nuanced tasks such as production of monosyllabic versus polysyllabic words. Furthermore, we show that temporal decoding strategies for distinguishing monosyllabic from polysyllabic words were feasible for signals arising from normal-appearing cortex but not from glioma-infiltrated cortex. These findings inform our understanding of cognitive processing in chronic disease states and have implications for neuromodulation and prosthetics in patients with malignant gliomas.

A framework for standardised tissue sampling and processing during resection of diffuse intracranial glioma: joint recommendations from four RANO groups.

Surgical resection represents the standard of care for people with newly diagnosed diffuse gliomas, and the neuropathological and molecular profile of the resected tissue guides clinical management and forms the basis for research. The Response Assessment in Neuro-Oncology (RANO) consortium is an international, multidisciplinary effort that aims to standardise research practice in neuro-oncology. These recommendations represent a multidisciplinary consensus from the four RANO groups: RANO resect, RANO recurrent glioblastoma, RANO radiotherapy, and RANO/PET for a standardised workflow to achieve a representative tumour evaluation in a disease characterised by intratumoural heterogeneity, including recommendations on which tumour regions should be surgically sampled, how to define those regions on the basis of preoperative imaging, and the optimal sample volume. Practical recommendations for tissue sampling are given for people with low-grade and high-grade gliomas, as well as for people with newly diagnosed and recurrent disease. Sampling of liquid biopsies is also addressed. A standardised workflow for subsequent handling of the resected tissue is proposed to avoid information loss due to decreasing tissue quality or insufficient clinical information. The recommendations offer a framework for prospective biobanking studies.

"De novo replication repair deficient glioblastoma, IDH-wildtype" is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade.

Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant "ultrahypermutation". The median age at diagnosis was 50 years (range 27-78), compared with 63 years for the other 450 patients with conventional glioblastoma (p < 0.01). All tumors had histologic features of the giant cell variant of glioblastoma. They lacked EGFR amplification, lacked combined trisomy of chromosome 7 plus monosomy of chromosome 10, and only rarely had TERT promoter mutation or CDKN2A homozygous deletion, which are hallmarks of conventional IDH-wildtype glioblastoma. Instead, they harbored frequent inactivating mutations in TP53, NF1, PTEN, ATRX, and SETD2 and recurrent activating mutations in PDGFRA. DNA methylation profiling revealed they did not align with known reference adult glioblastoma methylation classes, but instead had unique globally hypomethylated epigenomes and mostly classified as "Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A". Five patients were treated with immune checkpoint blockade, four of whom survived greater than 3 years. The median overall survival was 36.8 months, compared to 15.5 months for the other 450 patients (p < 0.001). We conclude that "De novo replication repair deficient glioblastoma, IDH-wildtype" represents a biologically distinct subtype in the adult population that may benefit from prospective identification and treatment with immune checkpoint blockade.

Inhibition of Cysteine Proteases via Thiol-Michael Addition Explains the Anti-SARS-CoV-2 and Bioactive Properties of Arteannuin B.

Artemisia annua is the plant that produces artemisinin, an endoperoxide-containing sesquiterpenoid used for the treatment of malaria. A. annua extracts, which contain other bioactive compounds, have been used to treat other diseases, including cancer and COVID-19, the disease caused by the virus SARS-CoV-2. In this study, a methyl ester derivative of arteannuin B was isolated when A. annua leaves were extracted with a 1:1 mixture of methanol and dichloromethane. This methyl ester was thought to be formed from the reaction between arteannuin B and the extracting solvent, which was supported by the fact that arteannuin B underwent 1,2-addition when it was dissolved in deuteromethanol. In contrast, in the presence of N-acetylcysteine methyl ester, a 1,4-addition (thiol-Michael reaction) occurred. Arteannuin B hindered the activity of the SARS CoV-2 main protease (nonstructural protein 5, NSP5), a cysteine protease, through time-dependent inhibition. The active site cysteine residue of NSP5 (cysteine-145) formed a covalent bond with arteannuin B as determined by mass spectrometry. In order to determine whether cysteine adduction by arteannuin B can inhibit the development of cancer cells, similar experiments were performed with caspase-8, the cysteine protease enzyme overexpressed in glioblastoma. Time-dependent inhibition and cysteine adduction assays suggested arteannuin B inhibits caspase-8 and adducts to the active site cysteine residue (cysteine-360), respectively. Overall, these results enhance our understanding of how A. annua possesses antiviral and cytotoxic activities.

Association of CDKN2A alterations with increased postoperative seizure risk after resection of brain metastases.

OBJECTIVE: Seizures are common and significantly disabling for patients with brain metastases (BMs). Although resection can provide seizure control, a subset of patients with BMs may continue to suffer seizures postoperatively. Genomic BM characteristics may influence which patients are at risk for postoperative seizures. This work explores correlations between genomic alterations and risk of postoperative seizures following BM resection. METHODS: All patients underwent BM resection at a single institution, with available clinical and sequencing data on more than 500 oncogenes. Clinical seizures were documented pre- and postoperatively. A random forest machine learning classification was used to determine candidate genomic alterations associated with postoperative seizures, and clinical and top genomic variables were correlated with postoperative seizures by using Cox proportional hazards models. RESULTS: There were 112 patients with BMs who underwent 114 surgeries and had at least 1 month of postoperative follow-up. Seizures occurred preoperatively in 26 (22.8%) patients and postoperatively in 25 (21.9%). The Engel classification achieved at 6 months for those with preoperative seizures was class I in 13 (50%); class II in 6 (23.1%); class III in 5 (19.2%), and class IV in 2 (7.7%). In those with postoperative seizures, only 8 (32.0%) had seizures preoperatively, and preoperative seizures were not a significant predictor of postoperative seizures (HR 1.84; 95% CI 0.79-4.37; p = 0.156). On random forest classification and multivariate Cox analysis controlling for factors including recurrence, extent of resection, and number of BMs, CDKN2A alterations were associated with postoperative seizures (HR 3.22; 95% CI 1.27-8.16; p = 0.014). Melanoma BMs were associated with higher risk of postoperative seizures compared with all other primary malignancies (HR 5.23; 95% CI 1.37-19.98; p = 0.016). Of 39 BMs with CDKN2A alteration, 35.9% (14/39) had postoperative seizures, compared to 14.7% (11/75) without CDKN2A alteration. The overall rate of postoperative seizures in melanoma BMs was 42.9% (15/35), compared with 12.7% (10/79) for all other primary malignancies. CONCLUSIONS: CDKN2A alterations and melanoma primary malignancy are associated with increased postoperative seizure risk following resection of BMs. These results may help guide postoperative seizure prophylaxis in patients undergoing resection of BMs.

Genomic alterations associated with rapid progression of brain metastases.

OBJECTIVE: The aim of this study was to investigate associations between genomic alterations in resected brain metastases and rapid local and distant CNS recurrence identified at the time of postoperative adjuvant radiosurgery. METHODS: This was a retrospective study on patients who underwent resection of intracranial brain metastases. Next-generation sequencing of more than 500 coding genes was performed on brain metastasis specimens. Postoperative and preradiosurgery MR images were compared to identify rapid recurrence. Genomic data were associated with rapid local and distant CNS recurrence of brain metastases using nominal regression analyses. RESULTS: The cohort contained 92 patients with 92 brain metastases. Thirteen (14.1%) patients had a rapid local recurrence, and 64 (69.6%) patients had rapid distant CNS progression by the time of postoperative adjuvant radiosurgery, which occurred in a median time of 25 days (range 3-85 days) from surgery. RB1 and CTNNB1 mutations were seen in 8.7% and 9.8% of the cohort, respectively, and were associated with a significantly higher risk of rapid local recurrence (RB1: OR 13.6, 95% CI 2.0-92.39, p = 0.008; and CTNNB1: OR 11.97, 95% CI 2.25-63.78, p = 0.004) on multivariate analysis. No genes were found to be associated with rapid distant CNS progression. However, the presence of extracranial disease was significantly associated with a higher risk of rapid distant recurrence on multivariate analysis (OR 4.06, 95% CI 1.08-15.34, p = 0.039). CONCLUSIONS: Genomic alterations in RB1 or CTNNB1 were associated with a significantly higher risk of rapid recurrence at the resection site. Although no genomic alterations were associated with rapid distant recurrence, having active extracranial disease was a risk factor for new lesions by the time of adjuvant radiotherapy after resection.

Multiplatform molecular analyses refine classification of gliomas arising in patients with neurofibromatosis type 1.

Gliomas arising in the setting of neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade or high-grade, and follow an indolent or aggressive clinical course. Comprehensive profiling of genetic alterations beyond NF1 inactivation and epigenetic classification of these tumors remain limited. Through next-generation sequencing, copy number analysis, and DNA methylation profiling of gliomas from 47 NF1 patients, we identified 2 molecular subgroups of NF1-associated gliomas. The first harbored biallelic NF1 inactivation only, occurred primarily during childhood, followed a more indolent clinical course, and had a unique epigenetic signature for which we propose the terminology "pilocytic astrocytoma, arising in the setting of NF1". The second subgroup harbored additional oncogenic alterations including CDKN2A homozygous deletion and ATRX mutation, occurred primarily during adulthood, followed a more aggressive clinical course, and was epigenetically diverse, with most tumors aligning with either high-grade astrocytoma with piloid features or various subclasses of IDH-wildtype glioblastoma. Several patients were treated with small molecule MEK inhibitors that resulted in stable disease or tumor regression when used as a single agent, but only in the context of those tumors with NF1 inactivation lacking additional oncogenic alterations. Together, these findings highlight recurrently altered pathways in NF1-associated gliomas and help inform targeted therapeutic strategies for this patient population.

Spectroscopic imaging of D-2-hydroxyglutarate and other metabolites in pre-surgical patients with IDH-mutant lower-grade gliomas.

PURPOSE: Prognostically favorable IDH-mutant gliomas are known to produce oncometabolite D-2-hydroxyglutarate (2HG). In this study, we investigated metabolite-based features of patients with grade 2 and 3 glioma using 2HG-specific in vivo MR spectroscopy, to determine their relationship with image-guided tissue pathology and predictive role in progression-free survival (PFS). METHODS: Forty-five patients received pre-operative MRIs that included 3-D spectroscopy optimized for 2HG detection. Spectral data were reconstructed and quantified to compare metabolite levels according to molecular pathology (IDH1R132H, 1p/19q, and p53); glioma grade; histological subtype; and T2 lesion versus normal-appearing white matter (NAWM) ROIs. Levels of 2HG were correlated with other metabolites and pathological parameters (cellularity, MIB-1) from image-guided tissue samples using Pearson's correlation test. Metabolites predictive of PFS were evaluated with Cox proportional hazards models. RESULTS: Quantifiable levels of 2HG in 39/42 (93%) IDH+ and 1/3 (33%) IDH- patients indicated a 91.1% apparent detection accuracy. Myo-inositol/total choline (tCho) showed reduced values in astrocytic (1p/19q-wildtype), p53-mutant, and grade 3 (vs. 2) IDH-mutant gliomas (p < 0.05), all of which exhibited higher proportions of astrocytomas. Compared to NAWM, T2 lesions displayed elevated 2HG+ γ-aminobutyric acid (GABA)/total creatine (tCr) (p < 0.001); reduced glutamate/tCr (p < 0.001); increased myo-inositol/tCr (p < 0.001); and higher tCho/tCr (p < 0.001). Levels of 2HG at sampled tissue locations were significantly associated with tCho (R = 0.62; p = 0.002), total NAA (R = - 0.61; p = 0.002) and cellularity (R = 0.37; p = 0.04) but not MIB-1. Increasing levels of 2HG/tCr (p = 0.0007, HR 5.594) and thresholding (≥ 0.905, median value; p = 0.02) predicted adverse PFS. CONCLUSION: In vivo 2HG detection can reasonably be achieved on clinical scanners and increased levels may signal adverse PFS.

Decision making and surgical modality selection in glioblastoma patients: an international multicenter survey.

PURPOSE: Due to the lack of consensus on the management of glioblastoma patients, there exists variability amongst surgeons and centers regarding treatment decisions. Though, objective data about the extent of this heterogeneity is still lacking. We aim to evaluate and analyze the similarities and differences in neurosurgical practice patterns. METHODS: The survey was distributed to members of the neurosurgical societies of the Netherlands (NVVN), Europe (EANS), the United Kingdom (SBNS) and the United States (CNS) between January and March 2021 with questions about the selection of surgical modality and decision making in glioblastoma patients. RESULTS: Survey respondents (224 neurosurgeons) were from 41 countries. Overall, the most notable differences observed were the presence and timing of a multidisciplinary tumor board; the importance and role of various perioperative factors in the decision-making process, and the preferred treatment in various glioblastoma cases and case variants. Tumor boards were more common at academic centers. The intended extent of resection for glioblastoma resections in eloquent areas was limited more often in European neurosurgeons. We found a strong relationship between the surgeon's theoretical survey answers and their actual approach in presented patient cases. In general, the factors which were found to be theoretically the most important in surgical decision making were confirmed to influence the respondents' decisions to the greatest extent in practice as well. DISCUSSION: This survey illustrates the theoretical and practical heterogeneity among surgeons and centers in their decision making and treatment selection for glioblastoma patients. These data invite further evaluations to identify key variables that can be optimized and may therefore benefit from consensus.

Functional maps of direct electrical stimulation-induced speech arrest and anomia: a multicentre retrospective study.

Direct electrical stimulation, the transient 'lesional' method probing brain function, has been utilized in identifying the language cortex and preserving language function during epilepsy and neuro-oncological surgeries for about a century. However, comparison of functional maps of the language cortex across languages/continents based on cortical stimulation remains unclear. We conducted a retrospective multicentre study including four cohorts of direct electrical stimulation mapping from four centres across three continents, where three indigenous languages (English, French and Mandarin) are spoken. All subjects performed the two most common language tasks: number counting and picture naming during stimulation. All language sites were recorded and normalized to the same brain template. Next, Spearman's correlation analysis was performed to explore the consistency of the distributions of the language cortex across centres, a kernel density estimation to localize the peak coordinates, and a hierarchical cluster analysis was performed to detect the crucial epicenters. A total of 598 subjects with 917 speech arrest sites (complete interruption of ongoing counting) and 423 anomia sites (inability to name or misnaming) were included. Different centres presented highly consistent distribution patterns for speech arrest (Spearman's coefficient r ranged from 0.60 to 0.85, all pair-wise correlations P < 0.05), and similar patterns for anomia (Spearman's coefficient r ranged from 0.37 to 0.80). The combinational speech arrest map was divided into four clusters: cluster 1 mainly located in the ventral precentral gyrus and pars opercularis, which contained the peak of speech arrest in the ventral precentral gyrus; cluster 2 in the ventral and dorsal precentral gyrus; cluster 3 in the supplementary motor area; cluster 4 in the posterior superior temporal gyrus and supramarginal gyrus. The anomia map revealed two clusters: one was in the posterior part of the superior and middle temporal gyri, which peaked at the posterior superior temporal gyrus; and the other within the inferior frontal gyrus, peaked at the pars triangularis. This study constitutes the largest series to date of language maps generated from direct electrical stimulation mapping. The consistency of data provides evidence for common language networks across languages, in the context of both speech and naming circuit. Our results not only clinically offer an atlas for language mapping and protection, but also scientifically provide better insight into the functional organization of language networks.

Reducing complication rates for repeat craniotomies in glioma patients: a single-surgeon experience and comparison with the literature.

BACKGROUND: There is a concern that glioma patients undergoing repeat craniotomies are more prone to complications. The study's goal was to assess if the complication profiles for initial and repeat craniotomies were similar, to determine predictors of complications, and to compare results with those in the literature. METHODS: A retrospective study was conducted of glioma patients (WHO grade II-IV) who underwent either an initial or repeat craniotomy performed by the senior author from 2012 until 2019. Complications were recorded by discharge, 30 days, and 90 days postoperatively. New neurologic deficits were recorded by 90 days postoperatively. Multivariate regression was performed to identify factors associated with complications. A meta-analysis was performed to identify rates of complications based on number of prior craniotomies. RESULTS: Within the cohort of 714 patients, 400 (56%) had no prior craniotomies, 218 (30.5%) had undergone 1 prior craniotomy, and 96 (13.5%) had undergone ≥ 2 prior craniotomies. There were 27 surgical and 10 medical complications in 30 patients (4.2%) and 19 reoperations for complications in 19 patients (2.7%) with no deaths by 90 days. Complications, reoperation rates, and new neurologic deficits did not differ based on number of prior craniotomies. On multivariate analysis, older age (OR1.5, 95%CI 1.0-2.2) and significant leukocytosis due to steroid use (OR12.6, 95%CI 2.5-62.9) were predictors of complications. Complication rates in the cohort were lower than rates reported in the literature. CONCLUSION: Contrary to prior reports in the literature, repeat craniotomies can be as safe as initial operations if surgeons implement best practices.

A Feasibility Study on Deep Learning Based Brain Tumor Segmentation Using 2D Ellipse Box Areas.

In most deep learning-based brain tumor segmentation methods, training the deep network requires annotated tumor areas. However, accurate tumor annotation puts high demands on medical personnel. The aim of this study is to train a deep network for segmentation by using ellipse box areas surrounding the tumors. In the proposed method, the deep network is trained by using a large number of unannotated tumor images with foreground (FG) and background (BG) ellipse box areas surrounding the tumor and background, and a small number of patients (<20) with annotated tumors. The training is conducted by initial training on two ellipse boxes on unannotated MRIs, followed by refined training on a small number of annotated MRIs. We use a multi-stream U-Net for conducting our experiments, which is an extension of the conventional U-Net. This enables the use of complementary information from multi-modality (e.g., T1, T1ce, T2, and FLAIR) MRIs. To test the feasibility of the proposed approach, experiments and evaluation were conducted on two datasets for glioma segmentation. Segmentation performance on the test sets is then compared with those used on the same network but trained entirely by annotated MRIs. Our experiments show that the proposed method has obtained good tumor segmentation results on the test sets, wherein the dice score on tumor areas is (0.8407, 0.9104), and segmentation accuracy on tumor areas is (83.88%, 88.47%) for the MICCAI BraTS'17 and US datasets, respectively. Comparing the segmented results by using the network trained by all annotated tumors, the drop in the segmentation performance from the proposed approach is (0.0594, 0.0159) in the dice score, and (8.78%, 2.61%) in segmented tumor accuracy for MICCAI and US test sets, which is relatively small. Our case studies have demonstrated that training the network for segmentation by using ellipse box areas in place of all annotated tumors is feasible, and can be considered as an alternative, which is a trade-off between saving medical experts' time annotating tumors and a small drop in segmentation performance.

A single institution retrospective analysis on survival based on treatment paradigms for patients with anaplastic oligodendroglioma.

INTRODUCTION: Anaplastic oligodendrogliomas are high-grade gliomas defined molecularly by 1p19q co-deletion. There is no curative therapy, and standard of care includes surgical resection followed by radiation and chemotherapy. However, the benefit of up-front radiation with chemotherapy compared to chemotherapy alone has not been demonstrated in a randomized control trial. Given the potential long-term consequences of radiation therapy, such as cognitive impairment, arteriopathy, endocrinopathy, and hearing/visual impairment, there is an effort to balance longevity with radiation toxicity. METHODS: We performed a retrospective single institution analysis of survival of patients with anaplastic oligodendroglioma over 20 years. RESULTS: 159 patients were identified as diagnosed with an anaplastic oligodendroglioma between 1996 and 2016. Of those, 40 patients were found to have AO at original diagnosis and had documented 1p19q co-deletion with a median of 7.1 years of follow-up (range: 0.6-16.7 years). After surgery, 45 % of patients were treated with radiation and chemotherapy at diagnosis, and 50 % were treated with adjuvant chemotherapy alone. The group treated with chemotherapy alone had a trend of receiving more cycles of chemotherapy than patients treated with radiation and chemotherapy upfront (p = 0.051). Median overall survival has not yet been reached. The related risk of progression in the upfront, adjuvant chemotherapy only group was almost 5-fold higher than the patients who received radiation and chemotherapy (hazard ratio = 4.85 (1.74-13.49), p = 0.002). However, there was no significant difference in overall survival in patients treated with upfront chemotherapy compared to patients treated upfront with chemotherapy and radiation (p = 0.8). Univariate analysis of age, KPS, extent of resection, or upfront versus delayed radiation was not associated with improved survival. CONCLUSIONS: Initial treatment with adjuvant chemotherapy alone, rather than radiation and chemotherapy, may be an option for some patients with anaplastic oligodendroglioma, as it is associated with similar overall survival despite shorter progression free survival.

Endovascular embolization versus surgical clipping in a single surgeon series of basilar artery aneurysms: a complementary approach in the endovascular era.

BACKGROUND: Currently, most basilar artery aneurysms (BAAs) are treated endovascularly. Surgery remains an appropriate therapy for a subset of all intracranial aneurysms. Whether open microsurgery would be required or utilized, and to what extent, for BAAs treated by a surgeon who performs both endovascular and open procedures has not been reported. METHODS: Retrospective analysis of prospectively maintained, single-surgeon series of BAAs treated with endovascular or open surgery from the first 5 years of practice. RESULTS: Forty-two procedures were performed in 34 patients to treat BAAs-including aneurysms arising from basilar artery apex, trunk, and perforators. Unruptured BAAs accounted for 35/42 cases (83.3%), and the mean aneurysm diameter was 8.4 ± 5.4 mm. Endovascular coiling-including stent-assisted coiling-accounted for 26/42 (61.9%) treatments and led to complete obliteration in 76.9% of cases. Four patients in the endovascular cohort required re-treatment. Surgical clip reconstruction accounted for 16/42 (38.1%) treatments and led to complete obliteration in 88.5% of cases. Good neurologic outcome (mRS ≤ 2) was achieved in 88.5% and 75.0% of patients in endovascular and open surgical cohorts, respectively (p = 0.40). Univariate logistic regression analysis demonstrated that advanced age (OR 1.11[95% CI 1.01-1.23]) or peri-procedural adverse event (OR 85.0 [95% CI 6.5-118.9]), but not treatment modality (OR 0.39[95% CI 0.08-2.04]), was the predictor of poor neurologic outcome. CONCLUSIONS: Complementary implementation of both endovascular and open surgery facilitates individualized treatment planning of BAAs. By leveraging strengths of both techniques, equivalent clinical outcomes and technical proficiency may be achieved with both modalities.

Language Neuroplasticity in Brain Tumor Patients Revealed by Magnetoencephalography.

Little is known about language impairment in brain tumor patients, especially in the presurgical phase. Impairment in this population may be missed because standardized tests fail to capture mild deficits. Additionally, neuroplasticity may also contribute to minimizing language impairments. We examined 14 presurgical patients with brain tumors in the language-dominant hemisphere using magnetoencephalography (MEG) while they performed a demanding picture-word interference task, that is, participants name pictures while ignoring distractor words. Brain tumor patients had behavioral picture-naming effects typically observed in healthy controls. The MEG responses also showed the expected pattern in its timing and amplitude modulation typical of controls, but with an altered spatial distribution of right hemisphere sources, in contrast to the classic left hemisphere source found in healthy individuals. This finding supports tumor-induced neural reorganization of language before surgery. Crucially, the use of electrophysiology allowed us to show the "same" neuronal response in terms of its timing and amplitude modulation in the right hemisphere, supporting the hypothesis that the processes performed by the right hemisphere following reorganization are similar in nature to those (previously) performed by the left hemisphere. We also identified one participant with a fast-growing tumor affecting large parts of critical language areas and underlying ventral and dorsal white matter tracts who showed a deviant pattern in behavior and in the MEG event-related responses. In conclusion, our results attest to the validity of using a demanding picture-naming task in presurgical patients and provide evidence for neuroplasticity, with the right hemisphere performing similar computations as the left hemisphere typically performs.

The immunohistochemical, DNA methylation, and chromosomal copy number profile of cauda equina paraganglioma is distinct from extra-spinal paraganglioma.

Paragangliomas are neuroendocrine tumors of the autonomic nervous system that are variably clinically functional and have a potential for metastasis. Up to 40% occur in the setting of a hereditary syndrome, most commonly due to germline mutations in succinate dehydrogenase (SDHx) genes. Immunohistochemically, paragangliomas are characteristically GATA3-positive and cytokeratin-negative, with loss of SDHB expression in most hereditary cases. In contrast, the rare paragangliomas arising in the cauda equina (CEP) or filum terminale region have been shown to be hormonally silent, clinically indolent, and have variable keratin expression, suggesting these tumors may represent a separate pathologic entity. We retrospectively evaluated 17 CEPs from 11 male and 6 female patients with a median age of 38 years (range 21-82), none with a family history of neuroendocrine neoplasia. Six of the 17 tumors demonstrated prominent gangliocytic or ganglioneuromatous differentiation. By immunohistochemistry, none of the CEPs showed GATA3 positivity or loss of SDHB staining; all 17 CEPs were cytokeratin positive. Genome-wide DNA methylation profiling was performed on 12 of the tumors and compared with publicly available genome-wide DNA methylation data. Clustering analysis showed that CEPs form a distinct epigenetic group, separate from paragangliomas of extraspinal sites, pheochromocytomas, and other neuroendocrine neoplasms. Copy number analysis revealed diploid genomes in the vast majority of CEPs, whereas extraspinal paragangliomas were mostly aneuploid with recurrent trisomy 1q and monosomies of 1p, 3, and 11, none of which were present in the cohort of CEP. Together, these findings indicate that CEPs likely represent a distinct entity. Future genomic studies are needed to further elucidate the molecular pathogenesis of these tumors.