Impact of socioeconomics and race on clinical follow-up and trial enrollment and adherence in cerebral cavernous malformation.

OBJECTIVES: Cerebral cavernous malformation (CCM) affects more than a million Americans but advanced care for symptomatic lesions and access to research studies is largely limited to referral academic centers MATERIALS AND METHODS: A cohort of CCM patients screened for research studies at an accredited center of excellence for CCM was analyzed. Demographics, lesion location, history of hemorrhage, insurance type and area of deprivation index (ADI) were collected. Primary outcomes were clinical follow-up within a year from initial evaluation, and enrollment and adherence in clinical trials among eligible subjects RESULTS: A majority (52.8%) of CCM patients evaluated had a high socioeconomic status (SES) (ADI 1-3), and only 11.5% were African American. Patients who had a symptomatic bleed were more likely to follow-up (p=0.01), and those with brainstem lesion were more likely to enroll/adhere in a clinical trial (p=0.02). Rates of clinical follow-up were similar across different ADI groups, insurance coverage and race. Patients who were uninsured/self-paying, and African Americans were more likely to decline/drop from clinical trials (OR 2.4, 95% CI 0.46-10.20 and OR 2.2, 95% CI 0.33-10.75, respectively), but differences were not statistically significant CONCLUSIONS: Access of disadvantaged patients to center of excellence care and research remains limited despite geographic proximity to their community. Patients with lower SES and African Americans are as likely to follow-up clinically, but there were trends of differences in enrollment/adherence in clinical trials. Mitigation efforts should target systemic causes of low access to specialized care among uninsured and African American patients.

Cerebrovascular Complications in Early Survivors of Civilian Penetrating Brain Injury.

BACKGROUND: This study investigates the presence of cerebrovascular injuries in a large sample of civilian penetrating brain injury (PBI) patients, determining the prevalence, radiographic characteristics, and impact on short-term outcome. METHODS: We retrospectively reviewed patients with PBI admitted to our institution over a 2-year period. Computed tomography head scans, computer tomography angiograms and venograms of the intracranial vessels were evaluated to determine the wound trajectory, intracranial injury characteristics, and presence of arterial (AI) and venous sinus (VSI) injuries. Demographics, clinical presentation, and treatment were also reviewed. Discharge disposition was used as surrogate of short-term outcome. RESULTS: Seventy-two patients were included in the study. The mechanism of injury was gunshot wounds in 71 patients and stab wound in one. Forty-one of the 72 patients (60%) had at least one vascular injury. Twenty-six out of 72 patients suffered an AI (36%), mostly pseudoaneurysms and occlusions, involving the anterior and middle cerebral arteries. Of the 72 patients included, 45 had dedicated computed tomography venograms, and of those 22 had VSI (49%), mainly manifesting as superior sagittal sinus occlusion. In a multivariable regression model, intraventricular hemorrhage at presentation was associated with AI (OR 9.9, p = 0.004). The same was not true for VSI. CONCLUSION: Acute traumatic cerebrovascular injury is a prevalent complication in civilian PBI, frequently involving both the arterial and venous sinus systems. Although some radiographic features might be associated with presence of vascular injury, assessment of the intracranial vasculature in the acute phase of all PBI is essential for early diagnosis. Treatment of vascular injury remains variable depending on local practice.

An overview of meningiomas.

Meningiomas are the most common primary intracranial tumor. Important advances are occurring in meningioma research. These are expected to accelerate, potentially leading to impactful changes on the management of meningiomas in the near and medium term. This review will cover the histo- and molecular pathology of meningiomas, including recent 2016 updates to the WHO classification of CNS tumors. We will discuss clinical and radiographic presentation and therapeutic management. Surgery and radiotherapy, the two longstanding primary therapeutic modalities, will be discussed at length. In addition, data from prior and ongoing investigations of other treatment modalities, including systemic and targeted therapies, will be covered. This review will quickly update the reader on the contemporary management and future directions in meningiomas. [Formula: see text].

Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1.

Pediatric low-grade gliomas (PLGGs) are among the most common solid tumors in children but, apart from BRAF kinase mutations or duplications in specific subclasses, few genetic driver events are known. Diffuse PLGGs comprise a set of uncommon subtypes that exhibit invasive growth and are therefore especially challenging clinically. We performed high-resolution copy-number analysis on 44 formalin-fixed, paraffin-embedded diffuse PLGGs to identify recurrent alterations. Diffuse PLGGs exhibited fewer such alterations than adult low-grade gliomas, but we identified several significantly recurrent events. The most significant event, 8q13.1 gain, was observed in 28% of diffuse astrocytoma grade IIs and resulted in partial duplication of the transcription factor MYBL1 with truncation of its C-terminal negative-regulatory domain. A similar recurrent deletion-truncation breakpoint was identified in two angiocentric gliomas in the related gene v-myb avian myeloblastosis viral oncogene homolog (MYB) on 6q23.3. Whole-genome sequencing of a MYBL1-rearranged diffuse astrocytoma grade II demonstrated MYBL1 tandem duplication and few other events. Truncated MYBL1 transcripts identified in this tumor induced anchorage-independent growth in 3T3 cells and tumor formation in nude mice. Truncated transcripts were also expressed in two additional tumors with MYBL1 partial duplication. Our results define clinically relevant molecular subclasses of diffuse PLGGs and highlight a potential role for the MYB family in the biology of low-grade gliomas.

The Time Burden of Office Visits in Contemporary Pituitary Care, 2016 to 2019.

BACKGROUND: The concept of "time toxicity" has emerged to address the impact of time spent in the healthcare system; however, little work has examined the phenomenon in the field of otolaryngology. OBJECTIVE: To validate the use of Evaluation and Management (E/M) current procedural terminology codes as a method to assess time burden and to pilot this tool to characterize the time toxicity of office visits associated with a diagnosis of pituitary adenoma between 2016 and 2019. METHODS: A retrospective cohort study of outpatient office visits quantified differences between timestamps documenting visit length and their associated E/M code visit length. The IBM MarketScan database was queried to identify patients with a diagnosis of pituitary adenoma in 2016 and to analyze their new and return claims between 2016 and 2019. One-way ANOVA and two-sample t-tests were used to examine claim quantity, time in office, and yearly visit time. RESULTS: In the validation study, estimated visit time via E/M codes and actual visit time were statistically different (P < 0.01), with E/M codes underestimating actual time spent in 79.0% of visits. In the MarketScan analysis, in 2016, 2099 patients received a primary diagnosis of pituitary adenoma. There were 8490 additional-related claims for this cohort from 2016 to 2019. The plurality of new office visits were with endocrinologists (n = 857; 29.3%). Total time spent in office decreased yearly, from a mean of 113 min (2016) to 69 min (2019) (P < 0.001). CONCLUSIONS: E/M codes underestimate the length of outpatient visits; therefore, time toxicity experienced by pituitary patients may be greater than reported. Further studies are needed to develop additional assessment tools for time toxicity and promote increased efficiency of care for patients with pituitary adenomas.

Coagulopathy as a Surrogate of Severity of Injury in Penetrating Brain Injury.

Penetrating brain injury (PBI) is the most devastating type of traumatic brain injury. Development of coagulopathy in the acute setting of PBI, though common, remains of unclear significance as does its reversal. The aim of this study is to investigate the relationship between coagulopathy and clinical presentation, radiographical features, and outcome in civilian patients with PBI. Eighty-nine adult patients with PBI at a Level I trauma center in Chicago, Illinois who survived acute resuscitation and with available coagulation profile were analyzed. Coagulopathy was defined as international normalized ratio [INR] >1.3, platelet count <100,000 /µL, or partial thromboplastin time >37 sec. Median age (interquartile range; IQR) of our cohort was 27 (21-35) years, and 74 (83%) were male. The intent was assault in 74 cases (83%). The mechanism of PBI was gunshot wound in all patients. Forty patients (45%) were coagulopathic at presentation. In a multiple regression model, coagulopathy was associated with lower Glasgow Coma Scale (GCS)-Motor score (odds ratio [OR], 0.67; confidence interval [CI], 0.48-0.94; p = 0.02) and transfusion of blood products (OR, 3.91; CI, 1.2-12.5; p = 0.02). Effacement of basal cisterns was the only significant radiographical features associated with coagulopathy (OR, 3.34; CI, 1.08-10.37; p = 0.04). Mortality was found to be significantly more common in coagulopathic patients (73% vs. 25%; p < 0.001). However, in our limited sample, reversal of coagulopathy at 24 h was not associated with a statistically significant improvement in outcome. The triad of coagulopathy, low post-resuscitation GCS, and radiographical effacement of basal cisterns identify a particularly ominous phenotype of PBI. The role, and potential reversal of, coagulopathy in this group warrants further investigation.

Cranial Vault Reconstruction and Evacuation of Hemorrhage After a Bifrontal Gunshot Wound to the Brain.

Civilian gunshot wounds to the brain are associated with high overall mortality; however, outcomes can vary significantly depending on bullet trajectory. This report details the outcome of a patient who sustained a bifrontal gunshot wound with multiple associated calvarial and frontal sinus fractures. Although surgery for penetrating brain injury is most frequently employed for relief of mass effect and decompression of vital structures, this case report describes a more comprehensive technique involving duroplasty, obliteration of the frontal sinus, and cranial vault reconstruction with the aim of decreasing the rate of cerebrospinal fluid leak, infection, reoperation, and readmission.

Management of civilians with penetrating brain injury: A systematic review.

PURPOSE: There has been a dramatic increase in penetrating gunshot-inflicted civilian penetrating brain injuries (cvPBI). We undertook a systematic review with exclusive focus on the management of cvPBI. METHODS: We explored: (1) cervical spine immobilization, (2) seizure incidence and prophylaxis, (3) infection incidence and antibiotic prophylaxis, (4) coagulopathy (5) vascular complications, and (6) surgical management. We searched PubMed, EMBASE, and Cochrane (1985-2019). The PRISMA guidelines were followed. The Newcastle-Ottawa Scale was employed for qualitative assessment; risk of bias was evaluated based upon the RTI item bank. The full protocol was registered to PROSPERO (CRD42019118877). RESULTS: The literature is scant, and of overall low quality and high risk of bias. Incidence of c-spine injury with no direct trauma is low; incidence of seizures does not appear to be different from non-penetrating mechanisms; there is no robust data for prophylactic antibiotics; coagulopathy is prevalent and has been independently associated with outcome; there is a high incidence of vascular injuries with traumatic intracranial aneurysms the most common sequelae; neurosurgical decision-making appears largely influenced by operator's assessment of salvageability. Surgery has been associated with decreased mortality. CONCLUSIONS: Limited amount of published work is clinically meaningful; this systematic review identified key knowledge gaps.

Tau 6D and 6P isoforms inhibit polymerization of full-length tau in vitro.

Alzheimer's disease and other tauopathies are characterized by the intracellular accumulation of insoluble filaments of the microtubule-associated protein tau. The six canonical tau isoforms in the adult brain consist of an N-terminal "projection" domain followed by a proline-rich region, a microtubule-binding repeat region, and a C-terminal tail. However, alternative splicing in exon 6 produces an additional set of tau isoforms, termed 6D and 6P, which contain only the N-terminus and part of the proline-rich region. We have previously shown that constructs representing N-terminal fragments of tau, which resemble the naturally occurring 6P and 6D isoforms, inhibit polymerization of the full-length protein in an in vitro filament formation assay and traced the inhibitory activity to amino acids 18-42. Here we report that 6P and 6D tau isoforms inhibit polymerization of full-length tau (hTau40) in a similar manner, likely by stabilizing full-length tau in a soluble conformation. The absence of exons 2 and 3 decreased the effectiveness of the 6D isoforms but not the 6P variants or the N-terminal tau fragments from our previous study, indicating that the 18-42 region is not the sole determinant of inhibitory ability. Finally, this paper demonstrates that inhibition is blocked by pseudophosphorylation of tyrosines 18 and 29, providing a potential link between tyrosine phosphorylation and disease progression. Taken together, these results indicate that the 6P/6D isoforms are potential endogenous inhibitors of tau filament formation and suggest a mechanism by which this ability may be disrupted in disease.

A possible link between astrocyte activation and tau nitration in Alzheimer's disease.

Alzheimer's disease (AD) pathology has been characterized, in part, by the self-assembly of the tau molecule into neurofibrillary tangles (NFT). While different post-translational modifications have been identified that accelerate tau aggregation, nitration at tyrosine residues prevents or slows tau filament formation in vitro. Of the five tyrosine residues within the molecule, nitration at the first tyrosine residue (Tyr 18) results in a profound inhibition of filament self-assembly. To determine whether nitration at Tyr 18 occurs in AD pathology, monoclonal antibodies were raised against a synthetic tau peptide nitrated at Tyr 18. A clone, termed Tau-nY18, reacts specifically with tau proteins nitrated at Tyr 18 and fails to cross-react with other nitrated tyrosine residues spanning the length of the molecule or with other proteins known to be nitrated in neurodegenerative diseases. In situ, Tau-nY18 sparsely labels the neuronal pathological hallmarks of the disease, including NFT and dystrophic neurites. Surprisingly however, Tau-nY18 robustly labels nitrated tau within activated, GFAP positive astrocytes intimately associated with amyloid plaques. Furthermore, this antibody detects nitrated tau in soluble preparations from both severe AD brains (Braak stage V, VI) and age-matched controls. Collectively, these findings suggest that nitration at Tyr 18 may be linked to astrocyte activation, an early event associated with amyloid plaque formation.

Diagnostic Evaluation in Primary CNS Lymphoma.

The diagnosis of primary central nervous system lymphoma (PCNSL) may be fraught with difficulty. After initial imaging reveals enhancing intracranial mass lesions steroids are often initiated. This leads to a decreased diagnostic yield of tumor biopsies which may be associated with delay in treatment initiation. We review a case of PCNSL treated with a very brief steroid course. Initial nondiagnostic biopsy histopathology is juxtaposed against subsequent diagnostic pathology. Imaging before and after steroids is presented, as is imaging after tumor regrowth in a noncontiguous location. Elements in the clinical history and radiographic presentation which should raise suspicion for PCNSL are reviewed. Increased understanding of the potential pitfalls surrounding PCNSL diagnosis may limit their future occurrence.

Combined petrosal approach.

PURPOSE OF REVIEW: The combined petrosal approach to the lateral skull base merges a retrolabyrinthine-presigmoid posterior fossa craniotomy with an adjacent middle fossa craniotomy, which are rendered continuous by division of the tentorium. This is a hearing-preserving approach that affords wide access to the lateral aspect of the clivus, the prepontine space, and the cerebellopontine angle. RECENT FINDINGS: This article details the historical development of the combined petrosal approach alongside a description. In particular, the critically relevant anatomy is reviewed, including the course of the vein of Labbé, with a view toward avoiding the known complications associated with this approach. Outcomes for application of this approach as applied for various lesions are also reviewed as portrayed by the current literature. SUMMARY: The combined petrosal approach affords wide access to the lateral skull base in the middle and posterior fossa. The approach and the lesions addressed by this approach involve delicate and sensitive anatomy. We review the evolution of this approach and highlight advancements that have allowed the combined petrosal approach to be a safe addition to the surgeon's armamentarium.

Complication Avoidance in Endoscopic Skull Base Surgery.

Endoscopic endonasal approaches to the skull base pathology have developed and evolved dramatically over the past 2 decades, particularly with collaboration between neurosurgery and otolaryngology physicians. These advances have increased significantly the use of such approaches beyond just resection of pituitary adenomas, including a variety of skull base pathologies. As the field has evolved, so has our understanding of the complications accompanying endoscopic skull base surgery, as well as techniques to both avoid and manage these complications. These are discussed here.

MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism.

Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.

Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive amnestic dementia that involves post-translational hyperphosphorylation, enzymatic cleavage, and conformational alterations of the microtubule-associated protein tau. The truncation state of tau influences many of its pathologic characteristics, including its ability to assume AD-related conformations and to assemble into filaments. Cleavage also appears to be an important marker in AD progression. Although C-terminal truncation of tau at D421 has recently been attributed to the apoptotic enzyme caspase-3, N-terminal processing of the protein remains mostly uncharacterized. Here, we report immunohistochemical staining in a cohort of 35 cases ranging from noncognitively impaired to early AD with a panel of three N-terminal anti-tau antibodies: Tau-12, 5A6, and 9G3-pY18. Of these three, the phosphorylation-independent epitope of 5A6 was the earliest to emerge in the pathological lesions of tau, followed by the appearance of the Tau-12 epitope. The unmasking of the Tau-12 epitope in more mature 5A6-positive tangles was not correlated with tau phosphorylation at tyrosine 18 (9G3-pY18). Still, later in the course of tangle evolution, the extreme N terminus of tau was lost, correlating temporally with the appearance of a C-terminal caspase-truncated epitope lacking residues 422-441. In addition, caspase-6 cleaved the N terminus of tau in vitro, preventing immunoreactivity with both Tau-12 and 5A6. Mass spectrometry confirmed that the in vitro caspase-6 truncation site is D13, a semicanonical and hitherto undescribed caspase cleavage site in tau. Collectively, these results suggest a role for caspase-6 and N-terminal truncation of tau during neurofibrillary tangle evolution and the progression of Alzheimer's disease.

Tau truncation during neurofibrillary tangle evolution in Alzheimer's disease.

The microtubule-associated protein, tau, is a highly soluble molecule that is nonetheless capable of self-association into filamentous deposits characteristic of a number of neurodegenerative diseases. This state change is thought to be driven by phosphorylation and/or C-terminal truncation events resulting in intracellular inclusions, such as the neurofibrillary tangles (NFTs) in Alzheimer's disease (AD). Previously, we reported the existence of a novel truncation event, cleavage at aspartic acid(421), presumably by a caspase, and also described a monoclonal antibody (Tau-C3) specific for tau cleaved at this site. Here, we report the timing of this cleavage event relative to other antibody-targeted alterations in the tau molecule during the course of NFT evolution in AD. Immunohistochemical studies indicate that cleavage at aspartic acid(421) occurs after formation of the Alz50 epitope but prior to formation of the Tau-66 epitope and truncation at glutamic acid(391) (formation of the MN423 epitope). Thus, creation of the Tau-C3 epitope appears to occur relatively early in the disease state, contemporaneous with the initial Alz50 folding event that heralds the appearance of filamentous tau in NFTs, neuropil threads, and the dystrophic neurites surrounding amyloid plaques.

Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets.

UNLABELLED: Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors, and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases. SIGNIFICANCE: Decisions for individualized therapies in patients with brain metastasis are often made from primary-tumor biopsies. We demonstrate that clinically actionable alterations present in brain metastases are frequently not detected in primary biopsies, suggesting that sequencing of primary biopsies alone may miss a substantial number of opportunities for targeted therapy.

Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations.

Meningiomas are the most common primary nervous system tumor. The tumor suppressor NF2 is disrupted in approximately half of all meningiomas, but the complete spectrum of genetic changes remains undefined. We performed whole-genome or whole-exome sequencing on 17 meningiomas and focused sequencing on an additional 48 tumors to identify and validate somatic genetic alterations. Most meningiomas had simple genomes, with fewer mutations, rearrangements and copy-number alterations than reported in other tumors in adults. However, several meningiomas harbored more complex patterns of copy-number changes and rearrangements, including one tumor with chromothripsis. We confirmed focal NF2 inactivation in 43% of tumors and found alterations in epigenetic modifiers in an additional 8% of tumors. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these pathways. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. These results begin to define the spectrum of genetic alterations in meningiomas and identify potential therapeutic targets.