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Introduction: Aggressive prolactinomas are life-limiting tumors without a standard of care treatment option after the oral alkylator, temozolomide, fails to provide tumor control., Methods: We reviewed an institutional database of pituitary tumors for patients with aggressive prolactinomas who progressed following treatment with a dopamine receptor agonist, radiotherapy and temozolomide. Within this cohort, we identified four patients who were treated with everolimus and we report their response to this therapy. Treatment response was determined by a neuroradiologist, who manually performed volumetric assessment and determined treatment response by Response Assessments in Neuro-Oncology (RANO) criteria., Results: Three of four patients who were treated with everolimus had a biochemical response to therapy and all patients derived a clinically meaningful benefit based upon suppression of tumor growth. While the best overall response as assessed by RANO criteria was stable disease for the four patients, a minor regression in tumor size was appreciated in two of the four patients., Conclusion: Everolimus is an active agent in the treatment of prolactinomas that warrants further investigation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Purpose: While contrast-enhanced MR imaging is the criterion standard in meningioma diagnosis and treatment response assessment, gallium 68 Ga-DOTATATE PET/MR imaging has increasingly demonstrated utility in meningioma diagnosis and management. Integrating 68 Ga-DOTATATE PET/MR imaging in postsurgical radiation planning reduces the planning target volume and organ-at-risk dose. However, 68 Ga-DOTATATE PET/MR imaging is not widely implemented in clinical practice due to higher perceived costs. Our study analyzes the cost-effectiveness of 68 Ga-DOTATATE PET/MR imaging for postresection radiation therapy planning in patients with intermediate-risk meningioma., Materials and Methods: We developed a decision-analytical model based on both recommended guidelines on meningioma management and our institutional experience. Markov models were implemented to estimate quality-adjusted life-years (QALY). Cost-effectiveness analyses with willingness-to-pay thresholds of $50,000/QALY and $100,000/QALY were performed from a societal perspective. Sensitivity analyses were conducted to validate the results. Model input values were based on published literature., Results: The cost-effectiveness results demonstrated that 68 Ga-DOTATATE PET/MR imaging yields higher QALY (5.47 versus 5.05) at a higher cost ($404,260 versus $395,535) compared with MR imaging alone. The incremental cost-effectiveness ratio analysis determined that 68 Ga-DOTATATE PET/MR imaging is cost-effective at a willingness to pay of $50,000/QALY and $100,000/QALY. Furthermore, sensitivity analyses showed that 68 Ga-DOTATATE PET/MR imaging is cost-effective at $50,000/QALY ($100,000/QALY) for specificity and sensitivity values above 76% (58%) and 53% (44%), respectively., Conclusions: 68 Ga-DOTATATE PET/MR imaging as an adjunct imaging technique is cost-effective in postoperative treatment planning in patients with meningiomas. Most important, the model results show that the sensitivity and specificity cost-effective thresholds of 68 Ga-DOTATATE PET/MR imaging could be attained in clinical practice., (© 2023 by American Journal of Neuroradiology.)

The incidence of brain metastases continues to present a management issue despite the advent of improved systemic control and overall survival. While the management of oligometastatic disease (ie, 1-4 brain metastases) with surgery and radiation has become fairly straightforward in the era of radiosurgery, the management of patients with multiple metastatic brain lesions can be challenging. Here we review the available evidence and provide a multidisciplinary management algorithm for brain metastases that incorporates the latest advances in surgery, radiation therapy, and systemic therapy while taking into account the latest in precision medicine-guided therapies. In particular, we argue that whole-brain radiation therapy can likely be omitted in most patients as up-front therapy., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

In the past, low-grade gliomas-World Health Organization (WHO) grade I and II tumors-were generally expected to have a much better prognosis than higher-grade (WHO grade III and IV) gliomas. However, diffuse gliomas (WHO grade II), unlike WHO grade I gliomas, are by definition infiltrative, limiting resection and potentially contributing to poor outcomes like those seen with malignant gliomas. Rapid progress in the understanding of the pathogenesis of these tumors indicates that specific molecular factors, especially isocitrate dehydrogenase mutation status and the presence or absence of the 1p/19q codeletion (deletion of the short arm of chromosome 1 and long arm of chromosome 19), are much more important than grade in determining prognosis and response to treatment. These molecular characteristics outweigh the histologic distinctions and have been quickly incorporated into the WHO classification of gliomas. Management of these tumors with surgery, radiation, and chemotherapy has similarly been transformed by these developments, highlighting the need for a customized approach for patients with low-grade gliomas., (Copyright © 2022. Published by Elsevier Inc.)

Secondary central nervous system lymphoma (SCNSL) is associated with poor prognosis and new therapeutic approaches are needed. The pivotal trial that led to US Food and Drug Administration (FDA) approval of axicabtagene ciloleucel excluded patients with SCNSL and human immunodeficiency virus. In this multi-institutional retrospective study, 14 SCNSL patients treated with axicabtagene ciloleucel, 3 of whom had human immunodeficiency virus, experienced rates of severe neurotoxicity and complete response of 32% and 58%, respectively. This is similar to rates observed in the pivotal ZUMA-1 trial that led to the approval of axi-cel at median follow-up of 5.9 months. Chimeric antigen receptor T-cell therapy is potentially a life-saving therapy for SCNSL patients and should not be withheld., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: This phase I/II trial in patients with recurrent glioblastoma (GBM) evaluates the safety and preliminary efficacy of marizomib, an irreversible pan-proteasome inhibitor that crosses the blood-brain barrier., Methods: Part A assessed the safety and efficacy of marizomib monotherapy. In Part B, escalating doses of marizomib (0.5-0.8 mg/m 2 ) in combination with bevacizumab were evaluated. Part C explored intra-patient dose escalation of marizomib (0.8-1.0 mg/m 2 ) for the combination., Results: In Part A, 30 patients received marizomib monotherapy. The most common AEs were fatigue (66.7%), headache (46.7%), hallucination (43.3%), and insomnia (43.3%). One patient (3.3%) achieved a partial response. In Part B, the recommended phase II dose of marizomib was 0.8 mg/m 2 when combined with bevacizumab 10 mg/kg. In Part C, dose escalation to 1.0 mg/m 2 was not tolerated. Pooled analysis of 67 patients treated with marizomib ≤0.8 mg/m 2 and bevacizumab showed a nonoverlapping safety profile consistent with the known safety profile of each agent: the most common grade ≥3 AEs were hypertension (16.4%), confusion (13.4%), headache (10.4%), and fatigue (10.4%). The overall response rate was 34.3%, including 2 patients with complete response. Six-month progression-free survival was 29.8%; median overall survival was 9.1 months., Conclusions: The safety profile of marizomib as monotherapy and in combination with bevacizumab was consistent with previous observations that marizomib crosses the blood-brain barrier. Preliminary efficacy did not demonstrate a meaningful benefit of the addition of marizomib to bevacizumab for the treatment of recurrent GBM., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background and Purpose: Glioblastomas (GBMs) that involve the subventricular zone (SVZ) have a poor prognosis, possibly due to recruitment of neural stem cells. The purpose of this study was to evaluate whether SVZ involvement by lower grade gliomas (LGG), WHO grade II and III, similarly predicts poorer outcomes. We further assessed whether tumor genetics and cellularity are associated with SVZ involvement and outcomes., Methods: Forty-five consecutive LGG patients with preoperative imaging and next generation sequencing were included in this study. Regional SVZ involvement and whole tumor apparent diffusion coefficient (ADC) values, as a measure of cellularity, were assessed on magnetic resonance imaging. Progression was determined by RANO criteria. Kaplan-Meier curves and Cox regression analyses were used to determine the hazard ratios (HR) for progression and survival., Results: Frontal, parietal, temporal, and overall SVZ involvement and ADC values were not associated with progression or survival (P ≥ .05). However, occipital SVZ involvement, seen in two patients, was associated with a higher risk of tumor progression (HR = 6.6, P = .016) and death (HR = 31.5, P = .015), CDKN2A/B mutations (P = .03), and lower ADC histogram values at the 5th (P = .026) and 10th percentiles (P = .046). Isocitrate dehydrogenase, phosphatase and tensin homolog, epidermal growth factor receptor, and cyclin-dependent kinase 4 mutations were also prognostic (P ≤ .05)., Conclusions: Unlike in GBM, overall SVZ involvement was not found to strongly predict poor prognosis in LGGs. However, occipital SVZ involvement, though uncommon, was prognostic and found to be associated with CDKN2A/B mutations and tumor hypercellularity. Further investigation into these molecular mechanisms underlying occipital SVZ involvement in larger cohorts is warranted., (© 2020 American Society of Neuroimaging.)

Background and Purpose: Telomerase reverse transcriptase (TERT) promoter mutations are associated with worse prognosis in glioblastoma. The purpose of this study was to evaluate whether TERT mutation status was associated with specific morphologic and quantitative imaging features., Methods: Twenty-nine patients with isocitrate dehydrogenase 1/2-wildtype glioblastoma (13 TERT-wildtype, 16 TERT-mutated), who underwent preoperative magnetic resonance (MR) imaging were included in this retrospective study. Qualitative imaging phenotypes were evaluated using the Visually Accessible Rembrandt Images (VASARIs) feature set. Histogram analysis of apparent diffusion coefficient (ADC) and dynamic contrast-enhanced MR perfusion values were performed on enhancing tumor volumes-of-interest, and differences between TERT-wildtype and TERT-mutated tumors were assessed., Results: VASARI analysis demonstrated that the majority of morphologic features were not significantly different between TERT-wildtype and TERT-mutated tumors, although a higher proportion of TERT-wildtype tumors featured nonenhancing tumor crossing midline (P = .014). TERT-mutated tumors demonstrated lower median rate constant k ep (.38 vs. .76, P = .03) and lower median volume transfer coefficient K trans (.13 vs. .31, P = .02). There was no significant difference in median plasma volume v p (P = .92) or ADC values (P = .66) between the two groups. We further found a significant interaction between median k ep and K trans and TERT status, respectively, suggesting greater risk of death with increasing blood-brain barrier dysfunction in TERT-mutated but not in TERT-wildtype tumors., Conclusion: Our study demonstrates evidence of altered permeability metrics associated with TERT mutation in glioblastoma, laying the foundation for future prospective studies assessing implications for therapeutic management and clinical outcomes., (© 2019 by the American Society of Neuroimaging.)

Objective: Both 18 F-FDG PET and perfusion MRI are commonly used techniques for posttreatment glioma surveillance. Using integrated PET-MRI, we assessed the rate of discordance between simultaneously acquired FDG PET images and dynamic contrast-enhanced (DCE) perfusion MR images and determined whether tumor genetics predicts discordance., Materials and Methods: Forty-one consecutive patients with high-grade gliomas (20 with grade IV gliomas and 21 with grade III gliomas) underwent a standardized tumor protocol performed using an integrated 3-T PET-MRI scanner. Quantitative measures of standardized uptake value, plasma volume, and permeability were obtained from segmented whole-tumor volumes of interest and targeted ROIs. ROC curve analysis and the Youden index were used to identify optimal cutoffs for FDG PET and DCE-MRI. Two-by-two contingency tables and percent agreement were used to assess accuracy and concordance. Twenty-six patients (63%) from the cohort underwent next-generation sequencing for tumor genetics., Results: The best-performing FDG PET and DCE-MRI cutoffs achieved sensitivities of 94% and 91%, respectively; specificities of 56% and 89%, respectively; and accuracies of 80% and 83%, respectively. FDG PET and DCE-MRI findings were discordant for 11 patients (27%), with DCE-MRI findings correct for six of these patients (55%). Tumor grade, tumor volume, bevacizumab exposure, and time since radiation predicted discordance between FDG PET and DCE-MRI findings, with an ROC AUC value of 0.78. Isocitrate dehydrogenase gene and receptor tyrosine kinase gene pathway mutations increased the ROC AUC value to 0.83., Conclusion: FDG PET and DCE-MRI show comparable accuracy and sensitivity in identifying tumor progression. These modalities were shown to have discordant findings for more than a quarter of the patients assessed. Tumor genetics may contribute to perfusion-metabolism discordance, warranting further investigation.

There are few therapeutic options available for the treatment of recurrent meningiomas that have failed treatment with surgery and external-beam radiation therapy (EBRT). As additional EBRT is clinically risky, brachytherapy offers an important alternative for optimizing local control. In skull base meningiomas, the endoscopic endonasal approach (EEA) has demonstrated an excellent extent of resection. However, in the case of recurrent, atypical, or residual meningiomas, the EEA alone may not be adequate to address microscopic, residual, highly proliferative disease. In this situation, local radioactive seed brachytherapy has been shown to improve control, but few reports of this technique exist. A 48-year-old right-handed man presented on multiple occasions with recurrence of an anaplastic skull base meningioma, after multiple prior gross-total resections and multiple rounds of radiotherapy had failed. The authors performed a maximally safe neurosurgical tumor resection via EEA supplemented by the intraoperative implantation of 131Cs low-dose permanent brachytherapy seeds. They describe a technique for permanent implantation of brachytherapy seeds and provide operative video of this technique. The authors submit that utilizing this technique in combination with EEA tumor resection renders a minimally invasive approach to improving local control in a patient with a recurrent anaplastic or atypical meningioma of the skull base.

Purpose: Molecular data has become an essential part of the updated World Health Organization (WHO) grading of central nervous system tumors. However, stereotactic needle biopsies provide only small volume specimens and limit the extent of histologic and molecular testing that can be performed. We assessed the use of a tubular retractor-based minimally invasive biopsy technique to provide improved tissue yield and diagnostic data compared to needle biopsy., Methods: Eighteen patients underwent an open transtubular biopsy compared to 146 stereotactic biopsies during the years of 2010-2018., Results: Tubular biopsies resulted in a higher volume of tissue provided to the pathologist than needle biopsies (1.26 cm 3 vs. 0.3 cm 3 ; p < 0.0001). There was a higher rate of non-diagnostic sample with stereotactic compared to transtubular biopsy (13% vs. 0%; p = 0.13). Six patients who underwent stereotactic biopsy required reoperation for diagnosis, while no transtubular biopsy patient required reoperation in order to obtain a diagnostic specimen. Postoperative hematoma was the most common post-operative complication in both groups., Conclusions: Stereotactic transtubular biopsies are a viable alternative to stereotactic needle biopsies with excellent rates of diagnostic success and acceptable morbidity relative to the needle biopsy technique. As molecular data begins to increasingly drive treatment decisions, additional biopsy techniques that afford large tissue volumes may be necessary to adapt to the new needs of pathologists and treating oncologists.

Glioblastoma is one of the most lethal human cancers, with poor survival despite surgery, radiation treatment, and chemotherapy. Advances in the treatment of this type of brain tumor are limited because of several resistance mechanisms. Such mechanisms involve limited drug entry into the central nervous system compartment by the blood-brain barrier and by actions of the normal brain to counteract tumor-targeting medications. In addition, the vast heterogeneity in glioblastoma contributes to significant therapeutic resistance by preventing adequate control of the entire tumor mass by a single drug and by facilitating escape mechanisms from targeted agents. The stem cell-like characteristics of glioblastoma promote resistance to chemotherapy, radiation, and immunotherapy through upregulation of efflux transporters, promotion of glioblastoma stem cell proliferation in neurogenic zones, and immune suppression, respectively. Metabolic cascades in glioblastoma prevent effective treatments through the optimization of glucose use, the use of alternative nutrient precursors for energy production, and the induction of hypoxia to enhance tumor growth. In the era of precision medicine, an assortment of molecular techniques is being developed to target an individual's unique tumor, with the hope that this personalized strategy will bypass therapeutic resistance. Although each resistance mechanism presents an array of challenges to effective treatment of glioblastoma, as the field recognizes and addresses these difficulties, future treatments may have more efficacy and promise for patients with glioblastoma., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Numerous studies have demonstrated the importance of gross total resection in improving patient survival in glioblastoma (GBM). Advances in surgical tools and techniques such as intra-operative imaging, fluorescent agents, and functional imaging sequences are allowing for better identification of tumor borders and vital eloquent cortex in order to safely achieve higher rates of complete resections. Furthermore, due to the limits of surgical resection alone, new minimally invasive techniques for treatment of GBM are under development. These advances are crucial for improving neurosurgical care and outcomes in this difficult patient population., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Glioblastoma evades conventional therapies through a variety of mechanisms, including suppression of the immune system. This immunosuppressive microenvironment provides a potential target for treatment. There are several immunotherapies being actively investigated, including inhibition of immune checkpoint regulators, development of antitumor vaccinations from both dendritic cell and tumor peptide components, adoptive transfer of supercharged and durable T lymphocytes, and generation of oncolytic viruses. Although immunotherapy has already demonstrated efficacy for a variety of other malignancies, its efficacy in glioblastoma is still unclear. Identifying predictive biomarkers and improving the management of immune-related adverse effects will help to realize the full potential of these therapies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Advances in metabolic imaging techniques have allowed for more precise characterization of gliomas, particularly as it relates to tumor recurrence or pseudoprogression. Furthermore, the emerging field of radiogenomics where radiographic features are systemically correlated with molecular markers has the potential to achieve the holy grail of neuro-oncologic neuro-radiology, namely molecular diagnosis without requiring tissue specimens. In this section, we will review the utility of metabolic imaging and discuss the current state of the art related to the radiogenomics of glioblastoma.

In this article, we review the basics of diffusion tensor imaging and functional MRI, their current utility in preoperative neurosurgical mapping, and their limitations. We also discuss potential future applications, including implementation of resting state functional MRI. We then discuss perfusion and diffusion-weighted imaging and their application in advanced neuro-oncologic practice. We explain how these modalities can be helpful in guiding surgical biopsies and differentiating recurrent tumor from treatment related changes.

External beam radiotherapy (RT) has long played a crucial role in the treatment of glioblastoma. Over the past several decades, significant advances in RT treatment and image-guidance technology have led to enormous improvements in the ability to optimize definitive and salvage treatments. This review highlights several of the latest developments and controversies related to RT, including the treatment of elderly patients, who continue to be a fragile and vulnerable population; potential salvage options for recurrent disease including reirradiation with chemotherapy; the latest imaging techniques allowing for more accurate and precise delineation of treatment volumes to maximize the therapeutic ratio of conformal RT; the ongoing preclinical and clinical data regarding the combination of immunotherapy with RT; and the increasing evidence of cancer stem-cell niches in the subventricular zone which may provide a potential target for local therapies. Finally, continued development on many fronts have allowed for modestly improved outcomes while at the same time limiting toxicity.

The importance of surgery and maximal extent of resection (EOR) is well established in primary low-grade glioma (LGG) management. However, the role of surgery in the management of recurrent LGG is less clear. A recent review on the management of recurrent LGG concluded there was insufficient evidence to recommend surgery. Here, we summarize the recent advances regarding the role of surgery, radiotherapy (RT) and chemotherapy in the management of recurrent LGG. There is increasing evidence to support maximal EOR for treating recurrent LGG, as it may improve progression free survival (PFS) after recurrence and overall survival (OS). Based on the studies presented in this review, we suggest that repeat surgery with maximal EOR should be standard of care for recurrent LGG treatment., (Copyright © 2016. Published by Elsevier B.V.)

Background and Purpose: Parameters other than luminal narrowing are needed to predict the risk of stroke more reliably, particularly in patients with <70% stenosis. The goal of our study was to identify clinical risk factors and CT features of carotid atherosclerotic plaques, in a retrospective cohort of patients free of stroke at baseline, that are independent predictors of incident stroke on follow-up., Materials and Methods: We identified a retrospective cohort of patients admitted to our emergency department with suspected stroke between 2001-2007 who underwent a stroke work-up including a CTA of the carotid arteries that was subsequently negative for acute stroke. All patients also had to receive a follow-up brain study at least 2 weeks later. From a random sample, we reviewed charts and imaging studies of patients with subsequent new stroke on follow-up as well as those who remained stroke-free. All patients were classified either as "new carotid infarct patients" or "no-new carotid infarct patients" based on the Causative Classification for Stroke. Independently, the baseline CTA studies were processed using a custom, CT-based automated computer classifier algorithm that quantitatively assesses a set of carotid CT features (wall thickness, plaque ulcerations, fibrous cap thickness, lipid-rich necrotic core, and calcifications). Univariate and multivariate statistical analyses were used to identify any significant differences in CT features between the patient groups in the sample. Subsequent ROC analysis allowed comparison to the classic NASCET stenosis rule in identifying patients with incident stroke on follow-up., Results: We identified a total of 315 patients without a new carotid stroke between baseline and follow-up, and 14 with a new carotid stroke between baseline and follow-up, creating the main comparison groups for the study. Statistical analysis showed age and use of antihypertensive drugs to be the most significant clinical variables, and maximal carotid wall thickness was the most relevant imaging variable. The use of age ≥ 75 years, antihypertensive medication use, and a maximal carotid wall thickness of at least 4 mm was able to successfully identify 10 of the 14 patients who developed a new incident infarct on follow-up. ROC analysis showed an area under the ROC curve of 0.706 for prediction of new stroke with this new model., Conclusions: Our new paradigm of using age ≥ 75 years, history of hypertension, and carotid maximal wall thickness of >4 mm identified most of the patients with subsequent new carotid stroke in our study. It is simple and may help clinicians choose the patients at greatest risk of developing a carotid infarct, warranting validation with a prospective observational study.

Background and Purpose: The purpose of this study was to determine if the assessment of intracranial collateral circulation by CT angiography and/or perfusion CT (PCT) can predict the risk of future ischemic stroke in a large, retrospective cohort study., Methods: We identified 135 consecutive patients who underwent CT angiography of the head and neck and PCT of the brain at baseline and with subsequent follow-up brain imaging. Clinical and demographic information and carotid wall features were collected. Collateral circulation was assessed anatomically at CT angiography and functionally by measuring the mean transit time delay at PCT. The clinical, carotid, CT angiography, and PCT variables were compared between those with and without new incident infarct at follow-up imaging using mixed effect logistic statistical models., Results: During the follow-up period, 15 patients developed a new infarct and 120 patients did not. Clinical features associated with the stroke risk were age, hypertension, hyperlipidemia, and atrial fibrillation. The carotid features associated with stroke risk were wall thickness. Anatomic assessment of collaterals on CT angiography was not associated with stroke risk, whereas the functional assessment of collaterals (mean transit time delay on PCT) was associated with stroke risk. In a multivariate model, age, atrial fibrillation, and mean transit time delay (OR, 22.8; P<0.001) were the only covariates that were independent predictors of future ischemic stroke., Conclusions: The mean transit time delay on PCT contains important physiological information and should not be discarded. Along with age and atrial fibrillation, this functional assessment of intracranial collateral circulation predicts the risk of future hemispheric infarct.