H3K27M-mutant diffuse midline gliomas should be further molecularly stratified: an integrated analysis of 669 patients.

INTRODUCTION: H3K27M-mutated diffuse midline gliomas (H3-DMGs) are aggressive tumors with a fatal outcome. This study integrating individual patient data (IPD) from published studies aimed to investigate the prognostic impact of different genetic alterations on survival of these patients. METHODS: We accessed PubMed and Web of Science to search for relevant articles. Studies were included if they have available data of follow-up and additional molecular investigation of H3-DMGs. For survival analysis, Kaplan-Meier analysis and Cox regression models were utilized, and corresponding hazard ratios (HR) and 95% confidence intervals (CI) were computed to analyze the impact of genetic events on overall survival (OS). RESULT: We included 30 studies with 669 H3-DMGs. TP53 mutations were the most common second alteration among these neoplasms. In univariate Cox regression model, TP53 mutation was an indicator of shortened survival (HR 1.446; 95% CI 1.143-1.829) whereas ACVR1 (HR 0.712; 95% CI 0.518-0.976) and FGFR1 mutations (HR 0.408; 95% CI 0.208-0.799) conferred prolonged survival. In addition, ATRX loss was also associated with a better OS (HR 0.620; 95% CI 0.386-0.996). Adjusted for age, gender, and tumor location, the presence of TP53 mutations, the absence of ACVR1 or FGFR1 mutations remained significantly poor prognostic factors. CONCLUSIONS: We outlined the prognostic importance of additional genetic alterations in H3-DMGs and recommended that these neoplasms should be further molecularly segregated. This may aid neuro-oncologists in appropriate risk stratification.

NRG/RTOG 1122: A phase 2, double-blinded, placebo-controlled study of bevacizumab with and without trebananib in patients with recurrent glioblastoma or gliosarcoma.

BACKGROUND: Targeting vascular endothelial growth factor (VEGF) alone does not improve overall survival (OS) in recurrent glioblastoma (rGBM). The angiopoiein (Ang)-TIE2 system may play a role in tumor survival under VEGF inhibition. We conducted a phase 2, double-blinded, placebo-controlled trial of bevacizumab plus trebananib (a novel Fc fusion protein that sequesters Ang1/Ang2) over bevacizumab alone in rGBM. METHODS: Patients ≥18 years of age with a Karnofsky performance status ≥70 and GBM or variants in first or second relapse were randomized to bevacizumab 10 mg/kg every 2 weeks plus trebananib 15 mg/kg every week or bevacizumab plus placebo. The primary endpoint was 6-month progression-free survival (PFS). RESULTS: After an initial 6-patient lead-in cohort confirmed the safety of combining bevacizumab and trebananib, 115 eligible patients were randomized to the control (n = 58) or experimental treatment (n = 57). In the control arm, 6-month PFS was 41.1%, median survival time was 11.5 months (95% CI, 8.4-14.2 months), median PFS was 4.8 months (95% CI, 3.8-7.1 months), and radiographic response (RR) was 5.9%. In the experimental arm, 6-month PFS was 22.6%, median survival time was 7.5 months (95% CI, 6.8-10.1 months), median PFS was 4.2 months (95% CI, 3.7-5.6 months), and RR was 4.2%. The rate of severe toxicities was not significantly different between arms. CONCLUSION: The combination of bevacizumab and trebananib was well tolerated but did not significantly improve 6-month PFS rate, PFS, or OS for patients with rGBM over bevacizumab alone. The shorter PFS in the experimental arm with a hazard ratio of 1.51 (P = .04) suggests that the addition of trebananib to bevacizumab is detrimental.

Application of microfluidic devices for glioblastoma study: current status and future directions.

Glioblastoma (GBM) is one of the most malignant primary brain tumors. This neoplasm is the hardest to treat and has a bad prognosis. Because of the characteristics of genetic heterogeneity and frequent recurrence, a successful cure for the disease is unlikely. Increasing evidence has revealed that the GBM stem cell-like cells (GSCs) and microenvironment are key elements in GBM recurrence and treatment failure. To better understand the mechanisms underlying this disease and to develop more effective therapeutic strategies for treatment, suitable approaches, techniques, and model systems closely mimicking real GBM conditions are required. Microfluidic devices, a model system mimicking the in vivo brain microenvironment, provide a very useful tool to analyze GBM cell behavior, their correlation with tumor malignancy, and the efficacy of multiple drug treatment. This paper reviews the applications of microfluidic devices in GBM research and summarizes progress and perspectives in this field.

Glioblastoma Multiforme heterogeneity profiling with solid-state micropores.

Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. It is characterized by widespread heterogeneity at the cellular and molecular levels. The detection of this heterogeneity is valuable for accurate diagnosis. Herein, solid-state 20 µm diameter micropore made in thin suspended silicon dioxide membrane is used as cell sensor device. The device relies on a cell's mechano-physical properties as an indicator to differentiate between the subtypes of GBM. A library of GBM cell lines (U251, U87, D54 EGFRviii, and G55) was created by measuring the differences in cell's micropore translocation properties from their distinct electrical profiles. Each GBM subtype has distinct phenotype and this was delineated in their cell translocation behaviors. The library was used to distinguish cells from samples of brain tumor patients. The micropore device accurately profiled GBM patient samples for cell subtypes by comparing data with the GBM library. The micropore approach is simple, can be implemented at low cost and can be used in the clinical setups and operation theaters to detect and identify GBM subtypes from patient samples.

Co-occurrence of astrocytoma and astroblastoma: Case report and literature review.

A 41-year-old man presented to us with left arm and leg weakness and mild word finding difficulties. His preoperative magnetic resonance imaging (MRI) demonstrated abnormal T1 and T2 signal changes in the right temporal lobe and basal ganglia, indicative of possible glioma. An awake craniotomy for right temporal lobectomy was performed and the tumor was resected. Full pathologic workup later revealed the patient had two distinct tumors occurring simultaneously, anaplastic astrocytoma and astroblastoma. We review the literature regarding the treatment of anaplastic astrocytoma and astroblastoma and discuss their co-occurrence.

Review of seizure outcomes after surgical resection of dysembryoplastic neuroepithelial tumors.

Dysembryoplastic neuroepithelial tumors (DNETs) are rare tumors that present with seizures in the majority of cases. We report the results of a review of seizure freedom rates following resection of these benign lesions. We searched the English literature using PubMed for articles presenting seizure freedom rates for DNETs as a unique entity. Patient demographics, tumor characteristics, and operative variables were assessed across selected studies. Twenty-nine articles were included in the analysis. The mean age at surgery across studies was a median of 18 years (interquartile range 11-25 years). The mean duration of epilepsy pre-operatively was a median 7 years (interquartile range 3-11 years). Median reported gross-total resection rate across studies was 79% (interquartile range 62-92%). Authors variously chose lesionectomy or extended lesionectomy operations within and across studies. The median seizure freedom rate was 86% (interquartile range 77-93%) with only one study reporting fewer than 60% of patients seizure free. Seizure outcomes were either reported at 1 year of follow-up or at last follow-up, which occurred at a median of 4 years (interquartile range 3-7 years). The number of seizure-free patients who discontinued anti-epileptic drugs varied widely from zero to all patients. Greater extent of resection was associated with seizure freedom in four studies.

Tumor necrosis-initiated complement activation stimulates proliferation of medulloblastoma cells.

OBJECTIVE AND DESIGN: We sought to determine the effect of necrosis-induced activation of the complement protein C3 in medulloblastoma. MATERIALS/METHODS: Twelve medulloblastoma surgical specimens were evaluated for complement activation using immunohistochemistry, with H&E stains performed on adjacent tissue sections to determine the relationship of complement activation to necrotic tissue. Flow cytometry and Western blot were performed on three established medulloblastoma lines and one surgically-procured cell culture to determine expression of C3a receptor (C3aR) in medulloblastoma. In vitro proliferation of siRNA C3aR knockdown cells was compared to that of control siRNA cells with cell line Daoy. RESULTS: Three surgical specimens were found to have necrosis on H&E sections. In each case, iC3b staining was identified on adjacent sections, limited to the necrotic region. In no case did necrosis occur without iC3b staining on adjacent sections. C3aR protein was demonstrated on both the three established cell lines and on the surgical culture. Proliferation assays of Daoy cells with siRNA knockdown vs. control siRNA revealed significantly reduced proliferation at 72 h (p = 0.001). CONCLUSIONS: Necrosis is associated with complement activation in medulloblastoma. Medulloblastoma cells express C3aR, and siRNA-mediated knockdown of C3aR inhibits proliferation of these cells in vitro.

Radiotherapy Plan Quality Assurance in NRG Oncology Trials for Brain and Head/Neck Cancers: An AI-Enhanced Knowledge-Based Approach.

The quality of radiation therapy (RT) treatment plans directly affects the outcomes of clinical trials. KBP solutions have been utilized in RT plan quality assurance (QA). In this study, we evaluated the quality of RT plans for brain and head/neck cancers enrolled in multi-institutional clinical trials utilizing a KBP approach. The evaluation was conducted on 203 glioblastoma (GBM) patients enrolled in NRG-BN001 and 70 nasopharyngeal carcinoma (NPC) patients enrolled in NRG-HN001. For each trial, fifty high-quality photon plans were utilized to build a KBP photon model. A KBP proton model was generated using intensity-modulated proton therapy (IMPT) plans generated on 50 patients originally treated with photon RT. These models were then applied to generate KBP plans for the remaining patients, which were compared against the submitted plans for quality evaluation, including in terms of protocol compliance, target coverage, and organ-at-risk (OAR) doses. RT plans generated by the KBP models were demonstrated to have superior quality compared to the submitted plans. KBP IMPT plans can decrease the variation of proton plan quality and could possibly be used as a tool for developing improved plans in the future. Additionally, the KBP tool proved to be an effective instrument for RT plan QA in multi-center clinical trials.

Polymorphous low-grade neuroepithelial tumor of the young: Rare tumor and review of the literature.

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described low-grade neuroepithelial tumor with an infiltrative growth pattern and oligodendrocyte-like cells that are CD34 immunopositive. Correlating histology and results from molecular testing is critical to correctly diagnosing PLNTY, as its histologic appearance is similar to oligodendrogliomas and shares genetic abnormalities common to other low-grade epilepsy associated tumors (LEATs). In this case report, we describe a 31-year-old female with intractable epilepsy found to have a temporal mass and diagnosed with PLNTY after histopathologic and molecular testing. We describe the radiographic, histologic, and genetic features in relation to the epileptic and oncologic outcomes for this patient. Then, we compare these features and outcomes to other cases of PLNTY described in the literature.

A systematic review of amino acid PET in assessing treatment response to temozolomide in glioma.

The response assessment in neuro-oncology (RANO) criteria have been the gold standard for monitoring treatment response in glioblastoma (GBM) and differentiating tumor progression from pseudoprogression. While the RANO criteria have played a key role in detecting early tumor progression, their ability to identify pseudoprogression is limited by post-treatment damage to the blood-brain barrier (BBB), which often leads to contrast enhancement on MRI and correlates poorly to tumor status. Amino acid positron emission tomography (AA PET) is a rapidly growing imaging modality in neuro-oncology. While contrast-enhanced MRI relies on leaky vascularity or a compromised BBB for delivery of contrast agents, amino acid tracers can cross the BBB, making AA PET particularly well-suited for monitoring treatment response and diagnosing pseudoprogression. The authors performed a systematic review of PubMed, MEDLINE, and Embase through December 2021 with the search terms "temozolomide" OR "Temodar," "glioma" OR "glioblastoma," "PET," and "amino acid." There were 19 studies meeting inclusion criteria. Thirteen studies utilized [18F]FET, five utilized [11C]MET, and one utilized both. All studies used static AA PET parameters to evaluate TMZ treatment in glioma patients, with nine using dynamic tracer parameters in addition. Throughout these studies, AA PET demonstrated utility in TMZ treatment monitoring and predicting patient survival.

A systematic review of the utility of amino acid PET in assessing treatment response to bevacizumab in recurrent high-grade glioma.

BACKGROUND: Currently, bevacizumab (BEV), an antiangiogenic agent, is used as an adjunctive therapy to re-irradiation and surgery in patients with recurrent high-grade gliomas (rHGG). BEV has shown to decrease enhancement on MRI, but it is often unclear if these changes are due to tumor response to BEV or treatment-induced changes in the blood brain barrier. Preliminary studies show that amino acid PET can aid in distinguishing these changes on MRI. METHODS: The authors performed a systematic review of PubMed and Embase through July 2020 with the search terms 'bevacizumab' or 'Avastin' and 'recurrent glioma' and 'PET,' yielding 38 papers, with 14 meeting inclusion criteria. RESULTS: Thirteen out of fourteen studies included in this review used static PET and three studies used dynamic PET to evaluate the use of BEV in rHGG. Six studies used the amino acid tracer [18F]FET, four studies used [11C]MET, and four studies used [18F]FDOPA. CONCLUSION: [18F]FET, [11C]MET, and [18F]FDOPA PET in combination with MRI have shown promising results for improving accuracy in diagnosing tumor recurrence, detecting early treatment failure, and distinguishing between tumor progression and treatment-induced changes in patients with rHGG treated with BEV.

Physical confinement during cancer cell migration triggers therapeutic resistance and cancer stem cell-like behavior.

Metastasized cancer cells have an increased resistance to therapies leading to a drastic decrease in patient survival rates. However, our understanding of the cause for this enhanced resistance is lacking. In this study, we report that physically tight confinement during cancer cell migration triggers therapeutic resistance and induces cancer stem cell-like behavior including up-regulation in efflux proteins and in cancer stem cell related markers. Moreover, the re-localization of Yes-associated protein (YAP) to the cell nucleus indicated an elevated level of cytoskeletal tension. The increased cytoskeletal tension suggested that mechanical interactions between cancer cells and tight surroundings during metastasis is one of the factors that contributes to therapeutic resistance and acquisition of cancer stem cell (CSC) like features. With this system and supporting data, we are able to study cells with therapeutic resistance and CSC-like properties for the future purpose of developing new strategies for the treatment of metastatic cancer.

Re-evaluating Biopsy for Recurrent Glioblastoma: A Position Statement by the Christopher Davidson Forum Investigators.

Patients with glioblastoma (GBM) need bold new approaches to their treatment, yet progress has been hindered by a relative inability to dynamically track treatment response, mechanisms of resistance, evolution of targetable mutations, and changes in mutational burden. We are writing on behalf of a multidisciplinary group of academic neuro-oncology professionals who met at the collaborative Christopher Davidson Forum at Washington University in St Louis in the fall of 2019. We propose a dramatic but necessary change to the routine management of patients with GBM to advance the field: to routinely biopsy recurrent GBM at the time of presumed recurrence. Data derived from these samples will identify true recurrence vs treatment effect, avoid treatments with little chance of success, enable clinical trial access, and aid in the scientific advancement of our understanding of GBM.

Pure Apraxia of Speech After Resection Based in the Posterior Middle Frontal Gyrus.

BACKGROUND AND IMPORTANCE: Apraxia of speech is a disorder of articulatory coordination and planning in speech sound production. Its diagnosis is based on deficits in articulation, prosody, and fluency. It is often described concurrent with aphasia or dysarthria, while pure apraxia of speech is a rare entity. CLINICAL PRESENTATION: A right-handed man underwent focal surgical resection of a recurrent grade III astrocytoma in the left hemisphere dorsal premotor cortex located in the posterior middle frontal gyrus. After the procedure, he experienced significant long-term speech production difficulties. A battery of standard and custom language and articulatory assessments were administered, revealing intact comprehension and naming abilities, and preserved strength in orofacial articulators, but considerable deficits in articulatory coordination, fluency, and prosody-consistent with diagnosis of pure apraxia of speech. Tractography and resection volumes compared with publicly available imaging data from the Human Connectome Project suggest possible overlap with area 55b, an under-recognized language area in the dorsal premotor cortex and has white matter connectivity with the superior longitudinal fasciculus. CONCLUSION: The case reported here details a rare clinical entity, pure apraxia of speech resulting from resection of posterior middle frontal gyrus. While not a classical language area, emerging literature supports the role of this area in the production of fluent speech, and has implications for surgical planning and the general neurobiology of language.

A Connectomic Atlas of the Human Cerebrum-Chapter 10: Tractographic Description of the Superior Longitudinal Fasciculus.

The superior longitudinal fasciculus/arcuate white matter complex (SLF/AC) is the largest and most complex white matter tract of the human cerebrum with multiple inter-linked connections encompassing multiple cognitive functions such as language, attention, memory, emotion, and visuospatial function. However, little is known regarding the overall connectivity of this complex. Recently, the Human Connectome Project parcellated the human cortex into 180 distinct regions. Utilizing diffusion spectrum magnetic resonance imaging tractography coupled with the human cortex parcellation data presented earlier in this supplement, we aim to describe the macro-connectome of the SLF/AC in relation to the linked parcellations present within the human cortex. The purpose of this study is to present this information in an indexed, illustrated, and tractographically aided series of figures and tables for anatomic and clinical reference.

A Connectomic Atlas of the Human Cerebrum-Chapter 1: Introduction, Methods, and Significance.

BACKGROUND: As knowledge of the brain has increased, clinicians have learned that the cerebrum is composed of complex networks that interact to execute key functions. While neurosurgeons can typically predict and preserve primary cortical function through the primary visual and motor cortices, preservation of higher cognitive functions that are less well localized in regions previously deemed "silent" has proven more difficult. This suggests these silent cortical regions are more anatomically complex and redundant than our previous methods of inquiry can explain, and that progress in cerebral surgery will be made with an improved understanding of brain connectomics. Newly published parcellated cortex maps provide one avenue to study such connectomics in greater detail, and they provide a superior framework and nomenclature for studying cerebral function and anatomy. OBJECTIVE: To describe the structural and functional aspects of the 180 distinct areas that comprise the human cortex model previously published under the Human Connectome Project (HCP). METHODS: We divided the cerebrum into 8 macroregions: lateral frontal, motor/premotor, medial frontal, insular, temporal, lateral parietal, medial parietal, and occipital. These regions were further subdivided into their relevant parcellations based on the HCP cortical scheme. Connectome Workbench was used to localize parcellations anatomically and to demonstrate their functional connectivity. DSI studio was used to assess the structural connectivity for each parcellation. RESULTS: The anatomy, functional connectivity, and structural connectivity of all 180 cortical parcellations identified in the HCP are compiled into a single atlas. Within each section of the atlas, we integrate this information, along with what is known about parcellation function to summarize the implications of these data on network connectivity. CONCLUSION: This multipart supplement aims to build on the work of the HCP. We present this information in the hope that the complexity of cerebral connectomics will be conveyed in a more manageable format that will allow neurosurgeons and neuroscientists to accurately communicate and formulate hypotheses regarding cerebral anatomy and connectivity. We believe access to this information may provide a foundation for improving surgical outcomes by preserving lesser-known networks.

A Connectomic Atlas of the Human Cerebrum-Chapter 16: Tractographic Description of the Vertical Occipital Fasciculus.

In this supplement, we show a comprehensive anatomic atlas of the human cerebrum demonstrating all 180 distinct regions comprising the cerebral cortex. The location, functional connectivity, and structural connectivity of these regions are outlined, and where possible a discussion is included of the functional significance of these areas. In this chapter, we specifically address regions integrating to form the vertical occipital fasciculus.

A Connectomic Atlas of the Human Cerebrum-Chapter 17: Tractographic Description of the Cingulum.

In this supplement, we show a comprehensive anatomic atlas of the human cerebrum demonstrating all 180 distinct regions comprising the cerebral cortex. The location, functional connectivity, and structural connectivity of these regions are outlined, and where possible a discussion is included of the functional significance of these areas. In this chapter, we specifically address regions integrating to form the cingulum.

A Connectomic Atlas of the Human Cerebrum-Chapter 18: The Connectional Anatomy of Human Brain Networks.

BACKGROUND: It is widely understood that cortical functions are mediated by complex, interdependent brain networks. These networks have been identified and studied using novel technologies such as functional magnetic resonance imaging under both resting-state and task-based conditions. However, no one has attempted to describe these networks in terms of their cortical parcellations. OBJECTIVE: To describe our approach to network modeling and discuss its significance for the future of neuronavigation in brain surgery using the cortical parcellation scheme detailed within this supplement. METHODS: Using network models previously elucidated by our group using coordinate-based meta-analytic techniques, we show the anatomic position and underlying white matter tracts of the cortical regions comprising 8 functional networks of the human cerebrum. These network models are displayed using Synaptive's clinically available BrightMatter tractography software (Synaptive Medical, Toronto, Canada). RESULTS: The relevant cortical parcellations of 8 different cerebral networks have been identified. The fiber tracts between these regions were used to construct anatomically precise models of the networks. Models are described for the dorsal attention, ventral attention, semantic, auditory, supplementary motor, ventral premotor, default mode, and salience networks. CONCLUSION: Our goal is to move towards more precise, anatomically specific models of brain networks that can be constructed for individual patients and utilized in navigational platforms during brain surgery. We believe network modeling and future advances in navigation technology can provide a foundation for improving neurosurgical outcomes by allowing us to preserve complex brain networks.

A Connectomic Atlas of the Human Cerebrum-Chapter 11: Tractographic Description of the Inferior Longitudinal Fasciculus.

In this supplement, we seek to show a comprehensive anatomic atlas of the human cerebrum demonstrating all 180 distinct regions comprising the cerebral cortex. The location, functional connectivity, and structural connectivity of these regions are outlined, and where possible a discussion is included of the functional significance of these areas. In this chapter, we specifically address regions integrating to form the inferior longitudinal fasciculus.