Detection of diagnostic and prognostic methylation-based signatures in liquid biopsy specimens from patients with meningiomas.

Recurrence of meningiomas is unpredictable by current invasive methods based on surgically removed specimens. Identification of patients likely to recur using noninvasive approaches could inform treatment strategy, whether intervention or monitoring. In this study, we analyze the DNA methylation levels in blood (serum and plasma) and tissue samples from 155 meningioma patients, compared to other central nervous system tumor and non-tumor entities. We discover DNA methylation markers unique to meningiomas and use artificial intelligence to create accurate and universal models for identifying and predicting meningioma recurrence, using either blood or tissue samples. Here we show that liquid biopsy is a potential noninvasive and reliable tool for diagnosing and predicting outcomes in meningioma patients. This approach can improve personalized management strategies for these patients.

Intracranial Breakthrough Through Cavernous Sinus Compartments: Anatomic Study and Implications for Pituitary Adenoma Surgery.

BACKGROUND: Pituitary adenomas (PAs) with cavernous sinus (CS) invasion can extend into the intradural space by breaking through the CS walls. OBJECTIVE: To elaborate on the potential breakthrough route through CS compartments for invasive PAs and describe relevant surgical anatomy and technical nuances, with an aim to improve resection rates. METHODS: Twelve colored silicon-injected human head specimens were used for endonasal and transcranial dissection of the CS walls; ligaments, dural folds, and cranial nerves on each compartment were inspected. Two illustrative cases of invasive PA are also presented. RESULTS: The potential breakthrough routes through the CS compartments had unique anatomic features. The superior compartment breakthrough was delimited by the anterior petroclinoidal ligament laterally, posterior petroclinoidal ligament posteriorly, and interclinoidal ligament medially; tumor extended into the parapeduncular space with an intimate spatial relationship with the oculomotor nerve and posterior communicating artery. The lateral compartment breakthrough was limited by the anterior petroclinoidal ligament superiorly and ophthalmic nerve inferiorly; tumor extended into the middle fossa, displacing the trochlear nerve and inferolateral trunk to reach the medial temporal lobe. The posterior compartment breakthrough delineated by the Gruber ligament, petrosal process of the sphenoid bone, and petrous apex inferiorly, posterior petroclinoidal ligament superiorly, and dorsum sellae medially; tumor displaced or encased the abducens nerve and inferior hypophyseal artery and compressed the cerebral peduncle. CONCLUSION: The superior lateral and posterior components of the CS are potential routes for invasion by PAs. Better identification of CS breakthrough patterns is crucial for achieving higher gross total resection and remission rates.

Detection of tumor-specific DNA methylation markers in the blood of patients with pituitary neuroendocrine tumors.

BACKGROUND: DNA methylation abnormalities are pervasive in pituitary neuroendocrine tumors (PitNETs). The feasibility to detect methylome alterations in circulating cell-free DNA (cfDNA) has been reported for several central nervous system (CNS) tumors but not across PitNETs. The aim of the study was to use the liquid biopsy (LB) approach to detect PitNET-specific methylation signatures to differentiate these tumors from other sellar diseases. METHODS: We profiled the cfDNA methylome (EPIC array) of 59 serum and 41 plasma LB specimens from patients with PitNETs and other CNS diseases (sellar tumors and other pituitary non-neoplastic diseases, lower-grade gliomas, and skull-base meningiomas) or nontumor conditions, grouped as non-PitNET. RESULTS: Our results indicated that despite quantitative and qualitative differences between serum and plasma cfDNA composition, both sources of LB showed that patients with PitNETs presented a distinct methylome landscape compared to non-PitNETs. In addition, LB methylomes captured epigenetic features reported in PitNET tissue and provided information about cell-type composition. Using LB-derived PitNETs-specific signatures as input to develop machine-learning predictive models, we generated scores that distinguished PitNETs from non-PitNETs conditions, including sellar tumor and non-neoplastic pituitary diseases, with accuracies above ~93% in independent cohort sets. CONCLUSIONS: Our results underpin the potential application of methylation-based LB profiling as a noninvasive approach to identify clinically relevant epigenetic markers to diagnose and potentially impact the prognostication and management of patients with PitNETs.

DNA methylation-based signatures classify sporadic pituitary tumors according to clinicopathological features.

BACKGROUND: Distinct genome-wide methylation patterns cluster pituitary neuroendocrine tumors (PitNETs) into molecular groups associated with specific clinicopathological features. Here we aim to identify, characterize, and validate methylation signatures that objectively classify PitNET into clinicopathological groups. METHODS: Combining in-house and publicly available data, we conducted an analysis of the methylome profile of a comprehensive cohort of 177 tumors (Panpit cohort) and 20 nontumor specimens from the pituitary gland. We also retrieved methylome data from an independent PitNET cohort (N = 86) to validate our findings. RESULTS: We identified three methylation clusters associated with adenohypophyseal cell lineages and functional status using an unsupervised approach. Differentially methylated probes (DMP) significantly distinguished the Panpit clusters and accurately assigned the samples of the validation cohort to their corresponding lineage and functional subtypes memberships. The DMPs were annotated in regulatory regions enriched with enhancer elements, associated with pathways and genes involved in pituitary cell identity, function, tumorigenesis, and invasiveness. Some DMPs correlated with genes with prognostic and therapeutic values in other intra- or extracranial tumors. CONCLUSIONS: We identified and validated methylation signatures, mainly annotated in enhancer regions that distinguished PitNETs by distinct adenohypophyseal cell lineages and functional status. These signatures provide the groundwork to develop an unbiased approach to classifying PitNETs according to the most recent classification recommended by the 2017 WHO and to explore their biological and clinical relevance in these tumors.

A serum-based DNA methylation assay provides accurate detection of glioma.

BACKGROUND: The detection of somatic mutations in cell-free DNA (cfDNA) from liquid biopsy has emerged as a noninvasive tool to monitor the follow-up of cancer patients. However, the significance of cfDNA clinical utility remains uncertain in patients with brain tumors, primarily because of the limited sensitivity cfDNA has to detect real tumor-specific somatic mutations. This unresolved challenge has prevented accurate follow-up of glioma patients with noninvasive approaches. METHODS: Genome-wide DNA methylation profiling of tumor tissue and serum cfDNA of glioma patients. RESULTS: Here, we developed a noninvasive approach to profile the DNA methylation status in the serum of patients with gliomas and identified a cfDNA-derived methylation signature that is associated with the presence of gliomas and related immune features. By testing the signature in an independent discovery and validation cohorts, we developed and verified a score metric (the "glioma-epigenetic liquid biopsy score" or GeLB) that optimally distinguished patients with or without glioma (sensitivity: 100%, specificity: 97.78%). Furthermore, we found that changes in GeLB score reflected clinicopathological changes during surveillance (eg, progression, pseudoprogression, and response to standard or experimental treatment). CONCLUSIONS: Our results suggest that the GeLB score can be used as a complementary approach to diagnose and follow up patients with glioma.

Ruptured Distal Superior Cerebellar Artery Dissecting Aneurysm Treated with a Flow-diverting Device: Case Report and Review of Literature.

Distal fusiform aneurysms of the superior cerebellar artery (SCA) are rare and present several challenges to clinicians, especially when ruptured. While several treatment options are available, including surgical clipping and endovascular coiling, numerous challenges still remain due to the presence of vital neighboring neurovascular structures. In addition, the complications that arise due to the compromise of brainstem perforators make these aneurysms difficult to treat. This case report demonstrates the successful treatment of a ruptured fusiform aneurysm of the SCA with a flow-diverting device. We also conducted a literature review of the use of flow-diverting devices for treating such aneurysms. When choosing a treatment modality for a ruptured aneurysm, clinicians must consider both the patient-specific variables as well as aneurysm morphology. Treatment options including microsurgical clipping, endovascular coiling, and flow diversion carry risks. Therefore, the clinician must decide which option best fits each situation.