Quantifying intra-tumoral genetic heterogeneity of glioblastoma toward precision medicine using MRI and a data-inclusive machine learning algorithm.

BACKGROUND AND OBJECTIVE: Glioblastoma (GBM) is one of the most aggressive and lethal human cancers. Intra-tumoral genetic heterogeneity poses a significant challenge for treatment. Biopsy is invasive, which motivates the development of non-invasive, MRI-based machine learning (ML) models to quantify intra-tumoral genetic heterogeneity for each patient. This capability holds great promise for enabling better therapeutic selection to improve patient outcome. METHODS: We proposed a novel Weakly Supervised Ordinal Support Vector Machine (WSO-SVM) to predict regional genetic alteration status within each GBM tumor using MRI. WSO-SVM was applied to a unique dataset of 318 image-localized biopsies with spatially matched multiparametric MRI from 74 GBM patients. The model was trained to predict the regional genetic alteration of three GBM driver genes (EGFR, PDGFRA and PTEN) based on features extracted from the corresponding region of five MRI contrast images. For comparison, a variety of existing ML algorithms were also applied. Classification accuracy of each gene were compared between the different algorithms. The SHapley Additive exPlanations (SHAP) method was further applied to compute contribution scores of different contrast images. Finally, the trained WSO-SVM was used to generate prediction maps within the tumoral area of each patient to help visualize the intra-tumoral genetic heterogeneity. RESULTS: WSO-SVM achieved 0.80 accuracy, 0.79 sensitivity, and 0.81 specificity for classifying EGFR; 0.71 accuracy, 0.70 sensitivity, and 0.72 specificity for classifying PDGFRA; 0.80 accuracy, 0.78 sensitivity, and 0.83 specificity for classifying PTEN; these results significantly outperformed the existing ML algorithms. Using SHAP, we found that the relative contributions of the five contrast images differ between genes, which are consistent with findings in the literature. The prediction maps revealed extensive intra-tumoral region-to-region heterogeneity within each individual tumor in terms of the alteration status of the three genes. CONCLUSIONS: This study demonstrated the feasibility of using MRI and WSO-SVM to enable non-invasive prediction of intra-tumoral regional genetic alteration for each GBM patient, which can inform future adaptive therapies for individualized oncology.

Integrated molecular and multiparametric MRI mapping of high-grade glioma identifies regional biologic signatures.

Sampling restrictions have hindered the comprehensive study of invasive non-enhancing (NE) high-grade glioma (HGG) cell populations driving tumor progression. Here, we present an integrated multi-omic analysis of spatially matched molecular and multi-parametric magnetic resonance imaging (MRI) profiling across 313 multi-regional tumor biopsies, including 111 from the NE, across 68 HGG patients. Whole exome and RNA sequencing uncover unique genomic alterations to unresectable invasive NE tumor, including subclonal events, which inform genomic models predictive of geographic evolution. Infiltrative NE tumor is alternatively enriched with tumor cells exhibiting neuronal or glycolytic/plurimetabolic cellular states, two principal transcriptomic pathway-based glioma subtypes, which respectively demonstrate abundant private mutations or enrichment in immune cell signatures. These NE phenotypes are non-invasively identified through normalized K2 imaging signatures, which discern cell size heterogeneity on dynamic susceptibility contrast (DSC)-MRI. NE tumor populations predicted to display increased cellular proliferation by mean diffusivity (MD) MRI metrics are uniquely associated with EGFR amplification and CDKN2A homozygous deletion. The biophysical mapping of infiltrative HGG potentially enables the clinical recognition of tumor subpopulations with aggressive molecular signatures driving tumor progression, thereby informing precision medicine targeting.

Image-based models of T-cell distribution identify a clinically meaningful response to a dendritic cell vaccine in patients with glioblastoma.

BACKGROUND: Glioblastoma is an extraordinarily heterogeneous tumor, yet the current treatment paradigm is a "one size fits all" approach. Hundreds of glioblastoma clinical trials have been deemed failures because they did not extend median survival, but these cohorts are comprised of patients with diverse tumors. Current methods of assessing treatment efficacy fail to fully account for this heterogeneity. METHODS: Using an image-based modeling approach, we predicted T-cell abundance from serial MRIs of patients enrolled in the dendritic cell (DC) vaccine clinical trial. T-cell predictions were quantified in both the contrast-enhancing and non-enhancing regions of the imageable tumor, and changes over time were assessed. RESULTS: A subset of patients in a DC vaccine clinical trial, who had previously gone undetected, were identified as treatment responsive and benefited from prolonged survival. A mere two months after initial vaccine administration, responsive patients had a decrease in model-predicted T-cells within the contrast-enhancing region, with a simultaneous increase in the T2/FLAIR region. CONCLUSIONS: In a field that has yet to see breakthrough therapies, these results highlight the value of machine learning in enhancing clinical trial assessment, improving our ability to prospectively prognosticate patient outcomes, and advancing the pursuit towards individualized medicine.

History of Ablation Therapies in Neurosurgery.

Laser interstitial thermal therapy (LITT) and high-intensity focused ultrasound thermal ablation are treatment options with great potential to treat glioblastoma, metastasis, epilepsy, essential tremor, and chronic pain. Results from recent studies show that LITT is a viable alternative to conventional surgical techniques in select patient populations. Although many of the bases for these treatments have existed since the 1930s, the most important advancement in these techniques has occurred in the last 15 years and the coming years hold much promise for these treatments.

The neurosurgical marriage: evaluating the interplay of work life and home life from the perspective of partners of neurosurgical residents.

OBJECTIVE: Burnout and work-life balance have been noted to be problems for residents across all fields of medicine, including neurosurgery. No studies to date have evaluated how these factors may contribute to issues outside of the hospital, specifically residents' home lives. This study aimed to evaluate the interplay between home life and work life of neurosurgical residents, specifically from the point of view of residents' significant others. METHODS: Online surveys were distributed to the significant others of neurosurgical residents at 12 US neurosurgery residencies. Residents' partners were asked about relationship dynamics, their views on neurosurgery residency (work-life balance and burnout), and their views of neurosurgery as a career. RESULTS: The majority of residents' significant others (84%) reported being satisfied with their relationship. Significant others who reported dissatisfaction with their relationship were more likely to report frustration with work-life balance and more likely to report their resident partner as having higher levels of burnout. CONCLUSIONS: From the perspective of neurosurgery residents' significant others, higher perceived levels of burnout and lower satisfaction with work-life balance are correlated with lower levels of relationship satisfaction. These findings speak to the complex interplay of work life and home life and can be used to inform future interventions into improving the quality of life for both the resident and the significant other.

Safety and patterns of survivorship in recurrent GBM following resection and surgically targeted radiation therapy: Results from a prospective trial.

BACKGROUND: Treatment of recurrent glioblastoma (GBM) remains problematic with survival after additional therapy typically less than 12 months. We prospectively evaluated whether outcomes might be improved with resection plus permanent implantation of a novel radiation device utilizing the gamma-emitting isotope Cs-131 embedded within bioresorbable collagen tiles. METHODS: Recurrent histologic GBM were treated in a single-arm trial. Following radiation, the surgical bed was lined with the tiles. Subsequent treatments were at the treating physician's discretion. RESULTS: 28 patients were treated (20 at first recurrence, range 1-3). Median age was 58 years, KPS was 80, female:male ratio was 10:18. Methylguanine methyltransferase (MGMT) was methylated in 11%, unmethylated in 18%, and unknown in 71%. Post implant, 17 patients (61%) received ≥1 course of systemic therapy. For all patients, Kaplan-Meier estimates of median time to local failure were 12.1 months, post-implant survival was 10.7 months for all patients and 15.1 months for patients who received systemic therapy; for all patients, median overall survival from diagnosis was 25.0 months (range 9.1-143.1). Sex, age, and number of prior progressions were not statistically significant. Local control was continuously maintained in 46% of patients. Two deaths within 30 days occurred, one from intracranial hemorrhage and one after persistent coma. Three symptomatic adverse events occurred: one wound infection requiring surgery and two late radiation brain injury, resolved non-surgically. CONCLUSION: This pre-commercial trial demonstrated acceptable safety and favorable post-treatment local control and survival. The device has received FDA clearance for use in newly diagnosed malignant and all recurrent intracranial neoplasms.

Subtemporal Transcollateral Sulcus Approach for Temporal Horn Tumors: 2-Dimensional Operative Video and Description of the Technique.

INTRODUCTION: Purely temporal intraventricular tumors are uncommon. Given their deep location, access to these brain tumors can be challenging in terms of preserving brain tissue. The subtemporal approach spares the lateral temporal cortex and is a less traumatic corridor to reach intraventricular temporal tumors. OBJECTIVE: To describe and assess the feasibility of the subtemporal transcollateral approach for the removal of a temporal horn tumor. METHODS: We describe the subtemporal transcollateral sulcus operative technique detailed step-by-step and depicted through both video and illustrations to surgically resect a left intraventricular temporal mass in a 44-year-old woman who presented with worsening memory deficits. The surgery was performed under general anesthesia and with the use of a microscope and neuronavigation. RESULTS: The patient did not suffer from any postoperative complications. Her vision was intact, and her memory deficit was unchanged. A brain MRI showed complete removal of the tumor. The pathological examination revealed a World Health Organization grade I meningioma. CONCLUSION: The subtemporal transsulcal approach seems to be an efficient and safe way to access intraventricular lesions within the temporal horn while avoiding any disruption of the optic radiations and temporal language areas.

A Novel Tissue Atlas and Online Tool for the Interrogation of Small RNA Expression in Human Tissues and Biofluids.

One promising goal for utilizing the molecular information circulating in biofluids is the discovery of clinically useful biomarkers. Extracellular RNAs (exRNAs) are one of the most diverse classes of molecular cargo, easily assayed by sequencing and with expressions that rapidly change in response to subject status. Despite diverse exRNA cargo, most evaluations from biofluids have focused on small RNA sequencing and analysis, specifically on microRNAs (miRNAs). Another goal of characterizing circulating molecular information, is to correlate expression to injuries associated with specific tissues of origin. Biomarker candidates are often described as being specific, enriched in a particular tissue or associated with a disease process. Likewise, miRNA data is often reported to be specific, enriched for a tissue, without rigorous testing to support the claim. Here we provide a tissue atlas of small RNAs from 30 different tissues and three different blood cell types. We analyzed the tissues for enrichment of small RNA sequences and assessed their expression in biofluids: plasma, cerebrospinal fluid, urine, and saliva. We employed published data sets representing physiological (resting vs. acute exercise) and pathologic states (early- vs. late-stage liver fibrosis, and differential subtypes of stroke) to determine differential tissue-enriched small RNAs. We also developed an online tool that provides information about exRNA sequences found in different biofluids and tissues. The data can be used to better understand the various types of small RNA sequences in different tissues as well as their potential release into biofluids, which should help in the validation or design of biomarker studies.

Microsurgical approaches to the pulvinar: A comparative analysis.

OBJECTIVE: To compare the area of exposure to the cisternal thalamus associated with four surgical techniques: supracerebellar-infratentorial (SCIT), occipital interhemispheric (OI), transchoroidal (TC) and subtemporal before and after parahippocampal resection (ST and STh, respectively). METHODS: All approaches were performed on both sides of three heads. Qualitative anatomical analyses were performed to understand anatomical limits, advantages, and flaws of each technique. Quantitative analyses for multiple repeated dependent variables assessed significant differences between areas of exposure. RESULTS: Exposure area was significantly more extensive using TC and STh approaches compared to ST, OI, and SCIT. STh achieved a significantly wider exposure compared to ST. Regarding dissection angle, surrounding structures and limitations, ST approaches do not provide adequate exposure, nor alignment with the thalamic axis. The OI and STh may provide a better field of exposure, but without adequate alignment and challenging deeper dissections. TC provides better exposure of the cisternal pulvinar with access to lateral pulvinar at the atrium's anterior wall but is a transcortical route that disrupts non-pathological tissue. SCIT provides an adequate area of exposure with the possibility of alignment with the thalamus axis, thus allowing an easier dissection of deeper lesions. CONCLUSIONS: For lesions at the pulvinar surface, OI and STh are adequate. For lesions restricted to medial pulvinar and deep along the thalamus axis, SCIT approaches are recommended. Lesions extending to the lateral pulvinar and ventricular atrium are best removed through TC approaches. The ST approach was not suitable to the cisternal pulvinar due to its limited angular exposure.

Occipital Artery-Posterior Inferior Cerebellar Artery (PICA) Bypass for the Treatment of a Ruptured Fusiform Aneurysm of the Left PICA: 2-Dimensional Operative Video.

Posterior inferior cerebellar artery (PICA) aneurysms are usually complex to treat because of their deep location, frequent entanglement with the lower cranial nerves, the presence of perforating arteries to the brainstem, and their often dissecting or fusiform morphology.1 These aneurysms can require revascularization of the PICA.2 The length and size of the occipital artery (OA) make it an excellent donor.3,4 Video 1 shows the technical nuances of an OA-PICA bypass for the treatment of a ruptured fusiform aneurysm of the left PICA. The patient is a 34-year-old male presenting with an abrupt headache and confusion (Hunt and Hess grade III and World Federation Neurology Surgeons grade II). Computed tomography of the brain revealed hydrocephalus and subarachnoid hemorrhage (Fisher IV) and digital subtraction angiography revealed a fusiform aneurysm on the tonsillomedullary segment of the left PICA. Given the dissecting nature of this aneurysm and the fact that it was ruptured, we felt it would be safer to be prepared to perform revascularization and to secure the aneurysm using an open surgical approach.5 There were no complications associated with this procedure. The patient remained neurologically intact, and imaging showed good flow through the bypass and no evidence of stroke. OA-PICA bypass is a useful strategy to treat ruptured fusiform PICA aneurysms since it avoids sacrificing the PICA and the use of dual-antiplatelet therapy. This video is one of the few videos published on OA-PICA bypass.6,7 It explains the technical aspects, open and endovascular alternatives, and rationale for this procedure.

Current status of augmented reality in cerebrovascular surgery: a systematic review.

Augmented reality (AR) is an adjuvant tool in neuronavigation to improve spatial and anatomic understanding. The present review aims to describe the current status of intraoperative AR for the treatment of cerebrovascular pathology. A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The following databases were searched: PubMed, Science Direct, Web of Science, and EMBASE up to December, 2020. The search strategy consisted of "augmented reality," "AR," "cerebrovascular," "navigation," "neurovascular," "neurosurgery," and "endovascular" in both AND and OR combinations. Studies included were original research articles with intraoperative application. The manuscripts were thoroughly examined for study design, outcomes, and results. Sixteen studies were identified describing the use of intraoperative AR in the treatment of cerebrovascular pathology. A total of 172 patients were treated for 190 cerebrovascular lesions using intraoperative AR. The most common treated pathology was intracranial aneurysms. Most studies were cases and there was only a case-control study. A head-up display system in the microscope was the most common AR display. AR was found to be useful for tailoring the craniotomy, dura opening, and proper identification of donor and recipient vessels in vascular bypass. Most AR systems were unable to account for tissue deformation. This systematic review suggests that intraoperative AR is becoming a promising and feasible adjunct in the treatment of cerebrovascular pathology. It has been found to be a useful tool in the preoperative planning and intraoperative guidance. However, its clinical benefits remain to be seen.

Complete seizure-free rates following interventional treatment of intracranial arteriovenous malformations: a systematic review and meta-analysis.

Seizures are common presenting symptoms of intracranial arteriovenous malformations (AVMs). This systematic review and meta-analysis aims to assess the current evidence regarding complete seizure freedom rates following surgical resection, stereotactic radiosurgery (SRS), and/or endovascular embolization of intracranial AVMs. A systematic review of PubMed, Ovid MEDLINE, and Ovid EMBASE was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Included manuscripts were methodically scrutinized for quality, spontaneous AVM-associated or hemorrhage-associated seizures, complete seizure-free rates following each interventional treatment, follow-up duration; determination methods of seizure outcomes, and average time-to-onset of recurrent seizures after each treatment. Manuscripts that described patients with nondisabling seizures or reduced seizure frequency in their seizure-free calculations were excluded. Seizure freedom rates following surgical resection, SRS, and endovascular embolization were compared via random-effect analysis. Thirty-four studies with a total of 1765 intracranial AVM patients presenting with spontaneous AVM-associated seizures and 408 patients presenting with hemorrhage-associated seizures were qualitatively analyzed. For patients presenting with AVM-associated seizures, the complete seizure-free rates were 73.0% (321/440 patients; 95% CI 68.8-77.1%) following surgical resection, 60.5% (376/622 patients; 95% CI 56.6-64.3%) following SRS, and 44.6% (29/65 patients; 95% CI 32.5-56.7%) following endovascular embolization alone. For patients presenting with either AVM-associated or hemorrhage-associated seizures, the complete seizure-free rates were 73.0% (584/800 patients; 95% CI 69.9-76.1%) following surgical resection, 46.4% (572/1233 patients; 95% CI 43.6-49.2%) following SRS, and 44.6% (29/65 patients; 95% CI 32.5-56.7%) following embolization. For patients presenting with either AVM-associated or hemorrhage-associated seizures, the overall improvements in seizure outcomes regardless of complete seizure freedom were 82.6% (661/800 patients; 95% CI 80.0-85.3%), 70.6% (870/1233 patients; 95% CI 68.0-73.1%), and 70.8% (46/65 patients; 95% CI 59.7-81.1%) following surgical resection, SRS, and embolization, respectively. No study reported information about the time-to-onset for recurrent seizures in any patient following treatment, as seizure outcomes were only described at the last follow-up visit. The available data suggests that surgical resection results in the highest rate of complete seizure freedom. The rate of seizure improvement following surgery increased further to 82.3% when including patients who had improved seizure frequency without achieving true seizure freedom. Complete seizure-free rates following SRS or embolization were more ambiguous and lower when compared to surgical resection. There is a need for high quality studies evaluating AVM treatment modalities and clearly defined seizure outcomes, as the current literature consists mostly of heterogenous patient populations.

A proposed framework for cerebral venous congestion.

BACKGROUND: While venous congestion in the peripheral vasculature has been described and accepted, intracranial venous congestion remains poorly understood. The characteristics, pathophysiology, and management of cerebral venous stasis, venous hypertension and venous congestion remain controversial, and a unifying conceptual schema is absent. The cerebral venous and lymphatic systems are part of a complex and dynamic interaction between the intracranial compartments, with interplay between the parenchyma, veins, arteries, cerebrospinal fluid, and recently characterized lymphatic-like systems in the brain. Each component contributes towards intracranial pressure, occupying space within the fixed calvarial volume. This article proposes a framework to consider conditions resulting in brain and neck venous congestion, and seeks to expedite further study of cerebral venous diagnoses, mechanisms, symptomatology, and treatments. METHODS: A multi-institution retrospective review was performed to identify unique patient cases, complemented with a published case series to assess a spectrum of disease states with components of venous congestion affecting the brain. These diseases were organized according to anatomical location and purported mechanisms. Outcomes of treatments were also analyzed. Illustrative cases were identified in the venous treatment databases of the authors. CONCLUSION: This framework is the first clinically structured description of venous pathologies resulting in intracranial venous and cerebrospinal fluid hypertension. Our proposed system highlights unique clinical symptoms and features critical for appropriate diagnostic work-up and potential treatment. This novel schema allows clinicians effectively to approach cases of intracranial hypertension secondary to venous etiologies, and furthermore provides a framework by which researchers can better understand this developing area of cerebrovascular disease.

Interventional and surgical management of internal jugular venous stenosis: a narrative review.

BACKGROUND: A small subset of patients with presumed idiopathic intracranial hypertension are found to have isolated internal jugular vein stenosis (IJVS). OBJECTIVE: To review the current interventions used in patients who present with intracranial hypertension secondary to IJVS. METHODS: In December 2020, we performed a literature search on Pubmed/Medline and Scopus databases for original articles studying surgical and endovascular interventions used for intracranial hypertension in the setting of internal jugular vein stenosis. No date, patient population, or study type was excluded. RESULTS: All studies that included at least one case in which a surgical or endovascular intervention was used to treat IJVS were included. Selection criteria for patients varied, most commonly defined by identification of compression of the internal jugular vein. The 17 studies included in this review ranged from case reports to large single-center cohort studies. The most used surgical intervention was styloidectomy. Styloidectomy had an overall better outcome success rate (79%) than angioplasty/stenting (66%). No complications were recorded in any of the surgical cases analyzed. Outcome measures varied, but all studies recorded clinical symptoms of the patients. CONCLUSION: Few current large cohort studies analyze surgical and endovascular interventions for patients with IJVS. Notably, the most common intervention is styloidectomy, followed by internal jugular vein stenting. By understanding the trends and experience of interventionalists and surgeons, more focused and larger studies can be performed to determine effective strategies with the best clinical outcomes.

Use of Industrial Filters by Health Care Workers During Shortages of N95 Respirators in Pandemic Times.

The coronavirus disease 2019 (COVID-19) pandemic has led to a significant shortage of personal protective equipment in multiple health care facilities around the world, with the highest impact on N95 respirator masks. The N95 respirator is a mask that blocks at least 95% of very small (0.3 µm) particles and is considered a standard for enhanced respiratory precautions. The N95 mask shortage has created a need for other options for nasal and oral respiratory protection with similar filtration efficiency and "medical-grade" clearance, which can be used in health care settings. However, the literature around various filter types, their filtration capabilities, and the organizations certifying their use is dense, confusing, and not easily accessible to the public. Here, we synthesize relevant literature to analyze and disseminate information on (1) alternative viable filter options to N95s, (2) the National Institute for Occupational Safety and Health certification process, (3) the relationship of National Institute for Occupational Safety and Health certification to Food and Drug Administration certification of filtration devices and surgical masks, and (4) how this relationship may affect future filtration usage in the medical community during a pandemic. Analysis of these standards is meant to inform regarding evidence of respirator efficacy but does not imply any official endorsement of these alternatives. With this article, we illuminate viable alternative respirator options during the COVID-19 pandemic to help alleviate the dependency on N95 face masks.

Navigating a Carotico-Clinoid Foramen and an Interclinoidal Bridge in the Endonasal Endoscopic Approach: An Anatomical and Technical Note.

Objective The carotico-clinoid foramen and interclinoid bridge are two anatomical variants of the sellar region. If these anatomical variants go unrecognized and are not managed safely by the surgeon during expanded endoscopic endonasal surgery for a posterior clinoidectomy, a carotid artery injury may occur. We summarize a method to safely navigate in the presence of the carotico-clinoid foramen and interclinoid bridge in an endoscopic endonasal approach. Study Design The study involves cadaveric dissection and management of the anatomical variants. Setting The study took place in a cadaveric dissection laboratory. Participants The object of study is one cadaveric head. Main Outcome Measures After discovering the two variants in both cavernous sinuses of a cadaveric head, we established a stepwise coping strategy to avoid carotid artery injury while performing an endoscopic endonasal bilateral interdural pituitary transposition, and we report the final view after endoscopic management. Results Debulking of the middle clinoid process can decrease the obstacle effect, and the pituitary transposition can be performed medial to the ossified carotico-clinoid ligament. Disconnection of the interclinoid bridge is the prerequisite to an effective posterior clinoidectomy, and distinguishing the transition between the sellar diaphragm and the interclinoid bridge is essential. Conclusion In the presence of both the carotico-clinoid foramen and the interclinoid bridge, a bilateral interdural pituitary transposition can still be performed, although preoperative strategic preparation, full inspection, and stepwise disconnections are of paramount importance in such a scenario to avoid cavernous carotid artery injury.