Introduction: Imaging surveillance of contrast-enhancing lesions after the treatment of malignant brain tumors with radiation is plagued by an inability to reliably distinguish between tumor recurrence and treatment effects. Magnetic resonance perfusion-weighted imaging (PWI)—among other advanced brain tumor imaging modalities—is a useful adjunctive tool for distinguishing between these two entities but can be clinically unreliable, leading to the need for tissue sampling to confirm diagnosis. This may be partially because clinical PWI interpretation is non-standardized and no grading criteria are used for assessment, leading to interpretation discrepancies. This variance in the interpretation of PWI and its subsequent effect on the predictive value has not been studied. Our objective is to propose structured perfusion scoring criteria and determine their effect on the clinical value of PWI. Methods: Patients treated at a single institution between 2012 and 2022 who had prior irradiated malignant brain tumors and subsequent progression of contrast-enhancing lesions determined by PWI were retrospectively studied from CTORE (CNS Tumor Outcomes Registry at Emory). PWI was given two separate qualitative scores (high, intermediate, or low perfusion). The first (control) was assigned by a neuroradiologist in the radiology report in the course of interpretation with no additional instruction. The second (experimental) was assigned by a neuroradiologist with additional experience in brain tumor interpretation using a novel perfusion scoring rubric. The perfusion assessments were divided into three categories, each directly corresponding to the pathology-reported classification of residual tumor content. The interpretation accuracy in predicting the true tumor percentage, our primary outcome, was assessed through Chi-squared analysis, and inter-rater reliability was assessed using Cohen’s Kappa. Results: Our 55-patient cohort had a mean age of 53.5 ± 12.2 years. The percentage agreement between the two scores was 57.4% (κ: 0.271). Upon conducting the Chi-squared analysis, we found an association with the experimental group reads (p-value: 0.014) but no association with the control group reads (p-value: 0.734) in predicting tumor recurrence versus treatment effects. Conclusions: With our study, we showed that having an objective perfusion scoring rubric aids in improved PWI interpretation. Although PWI is a powerful tool for CNS lesion diagnosis, methodological radiology evaluation greatly improves the accurate assessment and characterization of tumor recurrence versus treatment effects by all neuroradiologists. Further work should focus on standardizing and validating scoring rubrics for PWI evaluation in tumor patients to improve diagnostic accuracy. Full article

Accurate radiation therapy (RT) targeting is crucial for glioblastoma treatment but may be challenging using clinical imaging alone due to the infiltrative nature of glioblastomas. Precise targeting by whole-brain spectroscopic MRI, which maps tumor metabolites including choline (Cho) and N-acetylaspartate (NAA), can quantify early treatment-induced molecular changes that other traditional modalities cannot measure. We developed a pipeline to determine how spectroscopic MRI changes during early RT are associated with patient outcomes to provide insight into the utility of adaptive RT planning. Data were obtained from a study (NCT03137888) where glioblastoma patients received high-dose RT guided by the pre-RT Cho/NAA twice normal (Cho/NAA ≥ 2x) volume, and received spectroscopic MRI scans pre- and mid-RT. Overlap statistics between pre- and mid-RT scans were used to quantify metabolic activity changes after two weeks of RT. Log-rank tests were used to quantify the relationship between imaging metrics and patient overall and progression-free survival (OS/PFS). Patients with lower Jaccard/Dice coefficients had longer PFS (p = 0.045 for both), and patients with lower Jaccard/Dice coefficients had higher OS trending towards significance (p = 0.060 for both). Cho/NAA ≥ 2x volumes changed significantly during early RT, putting healthy tissue at risk of irradiation, and warranting further study into using adaptive RT planning. Full article

Histone deacetylase inhibitors (HDACis) are drugs that target the epigenetic state of cells by modifying the compaction of chromatin through effects on histone acetylation. Gliomas often harbor a mutation of isocitrate dehydrogenase (IDH) 1 or 2 that leads to changes in their epigenetic state presenting a hypermethylator phenotype. We postulated that glioma cells with IDH mutation, due to the presence of epigenetic changes, will show increased sensitivity to HDACis. This hypothesis was tested by expressing mutant IDH1 with a point alteration—converting arginine 132 to histidine—within glioma cell lines that contain wild-type IDH1. Glioma cells engineered to express mutant IDH1 produced D-2-hydroxyglutarate as expected. When assessed for response to the pan-HDACi drug belinostat, mutant IDH1-expressing glioma cells were subjected to more potent inhibition of growth than the corresponding control cells. Increased sensitivity to belinostat correlated with the increased induction of apoptosis. Finally, a phase I trial assessing the addition of belinostat to standard-of-care therapy for newly diagnosed glioblastoma patients included one patient with a mutant IDH1 tumor. This mutant IDH1 tumor appeared to display greater sensitivity to the addition of belinostat than the other cases with wild-type IDH tumors based on both standard magnetic resonance imaging (MRI) and advanced spectroscopic MRI criteria. These data together suggest that IDH mutation status within gliomas may serve as a biomarker of response to HDACis. Full article

Multidisciplinary tumor boards (TB) are an essential part of brain tumor care, but quantifying the impact of imaging on patient management is challenging due to treatment complexity and a lack of quantitative outcome measures. This work uses a structured reporting system for classifying brain tumor MRIs, the brain tumor reporting and data system (BT-RADS), in a TB setting to prospectively assess the impact of imaging review on patient management. Published criteria were used to prospectively assign three separate BT-RADS scores (an initial radiology report, secondary TB presenter review, and TB consensus) to brain MRIs reviewed at an adult brain TB. Clinical recommendations at TB were noted and management changes within 90 days after TB were determined by chart review. In total, 212 MRIs in 130 patients (median age = 57 years) were reviewed. Agreement was 82.2% between report and presenter, 79.0% between report and consensus, and 90.1% between presenter and consensus. Rates of management change increased with increasing BT-RADS scores (0—3.1%, 1a—0%, 1b—66.7%, 2—8.3%, 3a—38.5%, 3b—55.9, 3c—92.0%, and 4—95.6%). Of 184 (86.8%) cases with clinical follow-up within 90 days after the tumor board, 155 (84.2%) of the recommendations were implemented. Structured scoring of MRIs provides a quantitative way to assess rates of agreement interpretation alongside how often management changes are recommended and implemented in a TB setting. Full article

Glioblastoma (GBM) is a fatal disease, with poor prognosis exacerbated by difficulty in assessing tumor extent with imaging. Spectroscopic MRI (sMRI) is a non-contrast imaging technique measuring endogenous metabolite levels of the brain that can serve as biomarkers for tumor extension. We completed a three-site study to assess survival benefits of GBM patients when treated with escalated radiation dose guided by metabolic abnormalities in sMRI. Escalated radiation led to complex post-treatment imaging, requiring unique approaches to discern tumor progression from radiation-related treatment effect through our quantitative imaging platform. The purpose of this study is to determine true tumor recurrence timepoints for patients in our dose-escalation multisite study using novel methodology and to report on median progression-free survival (PFS). Follow-up imaging for all 30 trial patients were collected, lesion volumes segmented and graphed, and imaging uploaded to our platform for visual interpretation. Eighteen months post-enrollment, the median PFS was 16.6 months with a median time to follow-up of 20.3 months. With this new treatment paradigm, incidence rate of tumor recurrence one year from treatment is 30% compared to 60–70% failure under standard care. Based on the delayed tumor progression and improved survival, a randomized phase II trial is under development (EAF211). Full article

Functional MRI is a well-established tool used for pre-surgical planning to help the neurosurgeon have a roadmap of critical functional areas that should be avoided, if possible, during surgery to minimize morbidity for patients with brain tumors (though this also has applications for surgical resection of epileptogenic tissue and vascular lesions). This article reviews the locations of secondary language centers within the brain along with imaging findings to help improve our confidence in our knowledge on language lateralization. Brief overviews of these language centers and their contributions to the language networks will be discussed. These language centers include primary language centers of “Broca’s Area” and “Wernicke’s Area”. However, there are multiple secondary language centers such as the dorsal lateral prefrontal cortex (DLPFC), frontal eye fields, pre- supplemental motor area (pre-SMA), Basal Temporal Language Area (BTLA), along with other areas of activation. Knowing these foci helps to increase self-assurance when discussing the nature of laterality with the neurosurgeon. By knowing secondary language centers for language lateralization, via fMRI, one can feel confident on providing neurosurgeon colleagues with appropriate information on the laterality of language in preparation for surgery. Full article

The skull base provides a platform for supporting the brain while serving as a conduit for major neurovascular structures. In addition to malignant lesions originating in the skull base, there are many benign entities and developmental variants that may simulate disease. Therefore, a basic understanding of the relevant embryology is essential. Lesions centered in the skull base can extend to the adjacent intracranial and extracranial compartments; conversely, the skull base can be secondarily involved by primary extracranial and intracranial disease. CT and MRI are the mainstay imaging methods and are complementary in the evaluation of skull base lesions. Advances in cross-sectional imaging have been crucial in the management of patients with skull base pathology, as this represents a complex anatomical area that is hidden from direct clinical exam. Furthermore, the clinician must rely on imaging studies for therapy planning and to monitor treatment response. It is crucial to have a thorough understanding of skull base anatomy and its various pathologies, as well as to recognize the appearance of treatment-related changes. In this review, we aim to describe skull base tumors and tumor-like lesions in an anatomical compartmental approach and present imaging methods that aid in diagnosis, management, and follow-up. Full article

Employing the full arsenal of therapeutics to treat brain tumors is limited by the relative impermeability of the blood–brain and blood–tumor barriers. In physiologic states, the blood–brain barrier serves a protective role by passively and actively excluding neurotoxic compounds; however, this functionality limits the penetrance of therapeutics into the tumor microenvironment. Focused ultrasound technology provides a method for overcoming the blood–brain and blood–tumor barriers through ultrasound frequency to transiently permeabilize or disrupt these barriers. Concomitant delivery of therapeutics has allowed for previously impermeable agents to reach the tumor microenvironment. This review details the advances in focused ultrasound in both preclinical models and clinical studies, with a focus on its safety profile. We then turn towards future directions in focused ultrasound-mediated therapies for brain tumors. Full article

While the advent of immunotherapy has revolutionized cancer treatment, its use in the treatment of glioblastoma (GBM) has been less successful. Most studies using immunotherapy in GBM have been negative and the reasons for this are still being studied. In clinical practice, interpreting response to immunotherapy has been challenging, particularly when trying to differentiate between treatment-related changes (i.e., pseudoprogression) or true tumor progression. T cell tagging is one promising technique to noninvasively monitor treatment efficacy by assessing the migration, expansion, and engagement of T cells and their ability to target tumor cells at the tumor site. Full article

Introduction: Recent advances in tumor visualization have improved the extent of resection (EOR) of primary and secondary tumors of the central nervous system, while limiting the morbidity and mortality of the surgery. One area of recent interest has been the use of intraoperative fluorophores for tumor visualization such as 5-aminolevulinic acid (5-ala) and sodium fluorescein. We performed a systematic review and meta-analysis on the utility of fluorophore administration and EOR with each fluorophore to update the current literature. Methods: We conducted a systematic review and meta-analysis on the use of intraoperative 5-ala or fluorescein between 2021 and 2023 using the PubMed, SCOPUS, and WOS databases. The initial search yielded 8688 results. After inclusion and exclusion criteria were met, 44 studies remained for review. A meta-analysis was performed to compare the EOR between studies for each fluorophore and to compare the presence of intraoperative fluorescence by tumor type. Odds ratios (OR) were calculated for gross total resection (GTR), and two-way ANOVA tests were performed to compare rates of intraoperative fluorescence by fluorophore and tumor type. Results: In all groups except low-grade glioma, fluorescence was present after 5-ala administration; fluorescence was present for all groups after fluorescein administration. Two-way ANOVA analysis for both fluorophores demonstrated no statistically significant difference in presence of fluorescence between type of tumor resected. Meta-analysis of EOR did show a higher, but not significant, rate of GTR in the 5-ala group compared to controls (OR = 1.29, 95% CI = 0.49; 3.37). In the fluorescein group, there were statistically significant higher odds of GTR compared to the control group (OR = 2.10, 95% CI = 1.43; 3.10, I² = 0%). Conclusions: Both 5-ala and sodium fluorescein demonstrated intraoperative fluorescence among various tumor types in both cranial and spinal tumors, as well as efficacy in improving EOR. Both fluorophores merit further investigation for use in surgery of CNS tumors. Full article