Current Management of Brain Metastases: Overview and Teaching Cases

Over the past two decades, increased global incidence of malignancy, improved systemic disease treatment with prolonged survival, and increased central nervous system (CNS) surveillance in cancer patients have all contributed to a rise in cerebral metastatic disease. As many patients retain good neurologic function, the approach to their management has shifted markedly; a pre-terminal prognosis and palliative treatment have been replaced by individualized care plans to prolong functional survival. However, the rapid shifts in disease characteristics, treatment options and emerging evidence can be challenging to navigate, and a rational approach to brain metastases is needed. We discuss the changing epidemiology of brain metastases and consider approaches to prognostic classification. We review current treatment modalities and discuss the significant studies pertaining to each, with emphasis on Level 1 evidence when available and cooperative group trials, as well as studies on adverse effects. To integrate the information presented, we offer case scenarios that highlight pertinent decision-making factors. The shift in care goal for cerebral metastases from symptom palliation to prolongation of survival is not only feasible, but in many cases indicated. The appropriate application of various treatment modalities must be considered in the context of individual patients and their primary cancer

Low-Intensity MR-Guided Focused Ultrasound Mediated Disruption of the Blood-Brain Barrier for Intracranial Metastatic Diseases

Low-intensity MR-guided focused ultrasound in combination with intravenously injected microbubbles is a promising platform for drug delivery to the central nervous system past the blood-brain barrier. The blood-brain barrier is a key bottleneck for cancer therapeutics via limited inter- and intracellular transport. Further, drugs that cross the blood-brain barrier when delivered in a spatially nonspecific way, result in adverse effects on normal brain tissue, or at high concentrations, result in increasing risks to peripheral organs. As such, various anti-cancer drugs that have been developed or to be developed in the future would benefit from a noninvasive, temporary, and repeatable method of targeted opening of the blood-brain barrier to treat metastatic brain diseases. MR-guided focused ultrasound is a potential solution to these design requirements. The safety, feasibility and preliminary efficacy of MRgFUS aided delivery have been demonstrated in various animal models. In this review, we discuss this preclinical evidence, mechanisms of focused ultrasound mediated blood-brain barrier opening, and translational efforts to neuro-oncology patients

DNA methylation profiling to predict recurrence risk in meningioma: development and validation of a nomogram to optimize clinical management

Abstract Background Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma. Methods DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts. Results The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03–0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8–7.2, P &lt; 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22–0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3–11.1, P &lt; 0.001) with clinical implications. Conclusions The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone. </jats:sec

Current and emerging brain applications of MR-guided focused ultrasound

Abstract MRI guided focused ultrasound is an emerging technique that uses acoustic energy to noninvasively treat intracranial disorders. At high frequencies, it can be used to raise tissue temperatures and ablate discrete brain targets with sub-millimeter accuracy. This application is currently under investigation for a broad range of clinical applications, including brain tumors, movement disorders, and psychiatric conditions. At low frequencies MRI guided focused ultrasound can be used to modulate neuronal activity and in conjunction with injected microbubbles, can open the blood-brain barrier to enhance the delivery of therapeutic compounds. The last decade has seen dramatic advances in the science of MRI guided focused ultrasound, helping elucidate both its mechanisms and potential in pre-clinical models, and its translational promise across myriad clinical applications. This review provides an update of current and emerging MRI guided focused ultrasound applications for intracranial disorders and describes future directions and challenges for the field

Ethmoid meningoencephalocele in a patient with cerebrofacial arteriovenous metameric syndrome

BACKGROUND: Skull base meningoencephaloceles are a rare condition, frequently secondary to traumatic or iatrogenic causes. Cerebrofacial arteriovenous metameric syndrome (CAMS) is characterized by the presence of retinal, facial, and cerebral arteriovenous malformations (AVMs) with metameric distribution. To our knowledge, this is the first reported case associating these 2 conditions. CASE DESCRIPTION: A 45-year-old woman previously diagnosed with CAMS type 2 presented with a long history of cerebrospinal fluid (CSF) rhinorrhea. Magnetic resonance imaging and digital subtraction angiography demonstrated a right-sided facial and orbital AVM extending posteriorly along the optic tract into the suprasellar cistern, and a right-sided meningoencephalocele protruding into the olfactory recess and ethmoid sinus. An extended endoscopic endonasal approach was performed to resect the meningoencephalocele and to repair the CSF leak without complications. CONCLUSIONS: We report the unusual association between the development of a meningoencephalocele and a metameric syndrome, and comment on clinical implications in the management of this patient

The central nervous system tumor methylation classifier changes neuro-oncology practice for challenging brain tumor diagnoses and directly impacts patient care

Abstract Background Molecular signatures are being increasingly incorporated into cancer classification systems. DNA methylation-based central nervous system (CNS) tumor classification is being recognized as having the potential to aid in cases of difficult histopathological diagnoses. Here, we present our institutional clinical experience in integrating a DNA-methylation-based classifier into clinical practice and report its impact on CNS tumor patient diagnosis and treatment. Methods Prospective case review was undertaken at CNS tumor board discussions over a 3-year period and 55 tumors with a diagnosis that was not certain to two senior neuropathologists were recommended for methylation profiling based on diagnostic needs. Tumor classification, calibrated scores, and copy number variant (CNV) plots were obtained for all 55 cases. These results were integrated with histopathological findings to reach a final diagnosis. We retrospectively reviewed each patient's clinical course to determine final neuro-pathology diagnoses and the impact of methylation profiling on their clinical management, with a focus on changes that were made to treatment decisions. Results Following methylation profiling, 46 of the 55 (84%) challenging cases received a clinically relevant diagnostic alteration, with two-thirds having a change in the histopathological diagnosis and the other one-third obtaining clinically important molecular diagnostic or subtyping alterations. WHO grading changed by 27% with two-thirds receiving a higher grade. Patient care was directly changed in 15% of all cases with major changes in clinical decision-making being made for these patients to avoid unnecessary or insufficient treatment. Conclusions The integration of methylation-based CNS tumor classification into diagnostics has a substantial clinical benefit for patients with challenging CNS tumors while also avoiding unnecessary health care costs. The clinical impact shown here may prompt the expanded use of DNA methylation profiling for CNS tumor diagnostics within prominent neuro-oncology centers globally