Management of clinically aggressive meningiomas is a considerable challenge. PD-L1 induced immune suppression has increasingly gained attention in clinical management of cancer; however, to date, the ...clinical significance and regulatory mechanisms of PD-L1 in meningioma is not yet fully characterized. We sought to characterize PD-L1 expression in meningioma and elucidate its regulatory mechanisms. Immunohistochemical staining of PD-L1 expression in meningiomas showed 43% positivity in both tumor and immune cells and we observed intra and inter tumoral heterogeneity. Univariate and multivariate analyses confirmed that PD-L1 protein expression is an independent prognostic marker for worse recurrence free survival in meningioma. Furthermore, our transcriptomic analysis revealed a strong association between PD-L1 expression and that of NFKB2 and carbonic anhydrase 9 (CA9). We also demonstrated that both of these markers, when co-expressed with PD-L1, predict tumor progression. Our studies on several meningioma cell lines cultured in hypoxic conditions validated the association of CA9 and PD-L1 expression. Here we show the clinical significance of PD-L1 in meningioma as a marker that can predict tumor recurrence. We also show an association PD-L1 expression with NFKB2 expression and its induction under hypoxic conditions. These findings may open new avenues of molecular investigation in pathogenesis of meningioma.
Introduction
Despite manifold advances in oncology, cancers of the central nervous system remain among the most lethal. Unique features of the brain, including distinct cellular composition, ...immunological privilege, and physical barriers to therapeutic delivery, likely contribute to the poor prognosis of patients with neuro-oncological disease. Focused ultrasound is an emerging technology that allows transcranial delivery of ultrasound energy to focal brain targets with great precision.
Methods
A review of the clinical and preclinical focused ultrasound literature was performed to obtain data regarding the current state of the focused ultrasound in context of neuro-oncology. A narrative review was then constructed to provide an overview of current and future applications of this technology.
Results
Focused ultrasound can facilitate direct control of tumors by thermal or mechanical ablation, as well as enhance delivery of diverse therapeutics by disruption of the blood–brain barrier without local tissue damage. Indeed, ultrasound-sensitive drug formulations or sonosensitizers may be combined with ultrasound blood–brain barrier disruption to achieve high local drug concentration while limiting systemic exposure to therapeutics. Furthermore, focused ultrasound can induce radiosensitization, immunomodulation, and neuromodulation. Here we review applications of focused ultrasound with a focus on approaches currently under clinical investigation for the treatment of neuro-oncological disease, such as blood–brain barrier disruption for drug delivery and thermal ablation. We also discuss design of clinical trials, selection of patient cohorts, and emerging approaches to improve the efficacy of transcranial ultrasound, such as histotripsy, as well as combinatorial strategies to exploit synergistic biological effects of existing cancer therapies and ultrasound.
Conclusions
Focused ultrasound is a promising and actively expanding therapeutic modality for diverse neuro-oncological diseases.
Pituitary apoplexy is associated with visual, cranial nerve, and endocrine dysfunction. In this article, the results of surgical and conservative management of pituitary apoplexy in a single center ...are evaluated and a review of the literature is presented.
A retrospective analysis was made of patients with pituitary apoplexy who underwent surgery or conservative management at our center between January 2007 and June 2017. Surgery was typically selected for patients who presented with acute deterioration of visual status and/or level of consciousness. Patients with no visual field deficit and those who had medical contraindications to undergo a surgical procedure because of previous comorbidities typically had conservative treatment. Baseline characteristics and clinical and radiologic outcomes were reviewed. A review of the literature (1990-2018) was performed according to PRISMA guidelines. Studies comparing the results of conservative and surgical management were identified. Visual, cranial nerve, and endocrine outcomes and tumor recurrence were analyzed.
Forty-nine patients (73.1%) were managed surgically and 18 (26.9%) conservatively. After careful case selection, patients underwent surgical or conservative treatment. Patients who underwent conservative treatment had fewer visual deficits. At diagnosis, visual deficit (38.8% vs. 75.5%; P = 0.008) and cranial nerve palsy (27.7% vs. 51%; P = 0.058) were less common in the conservative group. Conservative and surgical treatments had similar visual and cranial nerve improvement rates (75% vs. 58.3%, P = 0.63 and 75% vs. 69.2%, P = 1.0, respectively). In the conservative group, tumor shrinkage was observed in 76.4% of cases. The systematic review retrieved 11 studies. No significant difference between conservative and surgical treatment for clinical outcomes (visual field recovery, odds ratio OR, 1.45; 95% confidence interval CI, 0.72-2.92; cranial nerve recovery, OR, 2.30; 95% CI, 0.93-5.65; and hypopituitarism, OR, 1.05; 95% CI, 0.64-1.74) or tumor recurrence (OR, 0.68; 95% CI, 0.20-2.34) was observed.
A tailored approach to pituitary apoplexy, one that does not include an absolute need for surgery, is appropriate. Conservative management is appropriate in selected patients presenting without visual deficits.
Cranial radiotherapy improves survival of the most common childhood cancers, including brain tumors and leukemia. Unfortunately, long-term survivors are faced with consequences of secondary ...neoplasia, including radiation-induced meningiomas (RIMs). We characterized 31 RIMs with exome/NF2 intronic sequencing, RNA sequencing and methylation profiling, and found NF2 gene rearrangements in 12/31 of RIMs, an observation previously unreported in sporadic meningioma (SM). Additionally, known recurrent mutations characteristic of SM, including AKT1, KLF4, TRAF7 and SMO, were not observed in RIMs. Combined losses of chromosomes 1p and 22q were common in RIMs (16/18 cases) and overall, chromosomal aberrations were more complex than that observed in SM. Patterns of DNA methylation profiling supported similar cell of origin between RIMs and SMs. The findings indicate that the mutational landscape of RIMs is distinct from SMs, and have significant therapeutic implications for survivors of childhood cranial radiation and the elucidation of the molecular pathogenesis of meningiomas.Radiation-induced meningiomas are often more aggressive than sporadic ones. In this study, the authors perform an exome, methylation and RNA-seq analysis of 31 cases of radiation-induced meningioma and show NF2 rearrangement, an observation previously unreported in the sporadic tumors.
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.
Schwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often painful neuronal tumors called schwannomas (SWNs). While germline mutations in
SMARCB1
or
...LZTR1,
plus somatic mutations in
NF2
and loss of heterozygosity in chromosome 22q have been identified in a subset of patients, little is known about the epigenomic and genomic alterations that drive SWNTS-related SWNs (SWNTS-SWNs) in a majority of the cases. We performed multiplatform genomic analysis and established the molecular signature of SWNTS-SWNs. We show that SWNTS-SWNs harbor distinct genomic features relative to the histologically identical non-syndromic sporadic SWNs (NS-SWNS). We demonstrate the existence of four distinct DNA methylation subgroups of SWNTS-SWNs that are associated with specific transcriptional programs and tumor location. We show several novel recurrent non-22q deletions and structural rearrangements. We detected the
SH3PXD2A-HTRA1
gene fusion in SWNTS-SWNs, with predominance in
LZTR1
-mutant tumors. In addition, we identified specific genetic, epigenetic, and actionable transcriptional programs associated with painful SWNTS-SWNs including PIGF, VEGF, MEK, and MTOR pathways, which may be harnessed for management of this syndrome.
Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma, and a lethal neurofibromatosis type 1-related malignancy, with little progress made on treatment strategies. Here, we ...apply a multiplatform integrated molecular analysis on 108 tumors spanning the spectrum of peripheral nerve sheath tumors to identify candidate drivers of MPNST that can serve as therapeutic targets. Unsupervised analyses of methylome and transcriptome profiles identify two distinct subgroups of MPNSTs with unique targetable oncogenic programs. We establish two subgroups of MPNSTs: SHH pathway activation in MPNST-G1 and WNT/ß-catenin/CCND1 pathway activation in MPNST-G2. Single nuclei RNA sequencing characterizes the complex cellular architecture and demonstrate that malignant cells from MPNST-G1 and MPNST-G2 have neural crest-like and Schwann cell precursor-like cell characteristics, respectively. Further, in pre-clinical models of MPNST we confirm that inhibiting SHH pathway in MPNST-G1 prevent growth and malignant progression, providing the rational for investigating these treatments in clinical trials.
Purpose
External ventricular drainage (EVD) is a life-saving procedure indicated for elevated intracranial pressure. A catheter is inserted into the ventricles to drain cerebrospinal fluid and ...release the pressure on the brain. However, the standard freehand EVD technique results in catheter malpositioning in up to 60.1% of procedures. This proof-of-concept study aimed to evaluate the registration accuracy of a novel image-based verification system “Bullseye EVD” in a preclinical cadaveric model of catheter placement.
Methods
Experimentation was performed on both sides of 3 cadaveric heads (
n
= 6). After a pre-interventional CT scan, a guidewire simulating the EVD catheter was inserted as in a clinical EVD procedure. 3D structured light images (Einscan, Shining 3D, China) were acquired of an optical tracker placed over the guidewire on the surface of the scalp, along with three distinct cranial regions (scalp, face, and ear). A computer vision algorithm was employed to determine the guidewire position based on the pre-interventional CT scan and the intra-procedural optical imaging. A post-interventional CT scan was used to validate the performance of the Bullseye optical imaging system in terms of trajectory and offset errors.
Results
Optical images which combined facial features and exposed scalp within the surgical field resulted in the lowest trajectory and offset errors of 1.28° ± 0.38° and 0.33 ± 0.19 mm, respectively. Mean duration of the optical imaging procedure was 128 ± 35 s.
Conclusions
The Bullseye EVD system presents an accurate patient-specific method to verify freehand EVD positioning. Use of facial features was critical to registration accuracy. Workflow automation and development of a user interface must be considered for future clinical evaluation.
Abstract Introduction A spinal epidural abscess (SEA) is a medical emergency. Despite urgent surgical intervention and adjuvant antibiotic therapy, neurological prognosis remains variable and ...guarded. The optimal approach to managing this condition is debated with substantial variability in clinical practice, dependent on patient demographic and pretreatment neurological status as well as radiological appearance. Method A systematic search in MEDLINE and similar databases was conducted for literature published from 1990 through 2015 using the search term “spinal epidural abscess”, limiting the search results to human studies published in the English language. Case series that consisted of fewer than 10 patients were excluded. The evidence strength was graded according to the Grades of Recommendation Assessment, Development and Evaluation criteria. Results The search yielded 1843 patients from 34 retrospective case series. Ten studies compared surgical and medical management, with no significant difference in patients with good outcome (OR 0.65, p = 0.11) or neurological improvement (OR 1.11, p = 0.69). Failure rates following initial medical management requiring surgical intervention, however, ranged from 10% to 50%. Three of four studies evaluating timing of surgery reported large effect sizes for neurological outcome if early surgery was performed (p < 0.01). Other prognostic factors from a neurologic perspective included admission neurological status, patient age, and diabetes mellitus. Conclusion Surgery with adjuvant antibiotics remains the optimal treatment for the neurologically symptomatic SEA patient. If antibiotic therapy alone is considered for the neurologically intact patient, we recommend inter-disciplinary medical and surgical consultations with an in-depth dialogue on the potential for failure in isolated medical management and the recommendation for close neurological monitoring.
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