Glioblastoma multiforme (GBM) is one of the most infiltrating, aggressive, and poorly treated brain tumors. Progress in genomics and proteomics has paved the way for identifying potential therapeutic ...targets for treating GBM, yet the vast majority of these leading drug candidates for the treatment of GBM are ineffective, mainly due to restricted passages across the blood–brain barrier. Nanoparticles have been emerged as a promising platform to treat different types of tumors due to their ability to transport drugs to target sites while minimizing adverse effects. Herein, we devised a localized strategy to deliver RNA interference (RNAi) directly to the GBM site using hyaluronan (HA)-grafted lipid-based nanoparticles (LNPs). These LNPs having an ionized lipid were previously shown to be highly effective in delivering small interfering RNAs (siRNAs) into various cell types. LNP’s surface was functionalized with hyaluronan (HA), a naturally occurring glycosaminoglycan that specifically binds the CD44 receptor expressed on GBM cells. We found that HA-LNPs can successfully bind to GBM cell lines and primary neurosphers of GBM patients. HA-LNPs loaded with Polo-Like Kinase 1 (PLK1) siRNAs (siPLK1) dramatically reduced the expression of PLK1 mRNA and cumulated in cell death even under shear flow that simulate the flow of the cerebrospinal fluid compared with control groups. Next, a human GBM U87MG orthotopic xenograft model was established by intracranial injection of U87MG cells into nude mice. Convection of Cy3-siRNA entrapped in HA-LNPs was performed, and specific Cy3 uptake was observed in U87MG cells. Moreover, convection of siPLK1 entrapped in HA-LNPs reduced mRNA levels by more than 80% and significantly prolonged survival of treated mice in the orthotopic model. Taken together, our results suggest that RNAi therapeutics could effectively be delivered in a localized manner with HA-coated LNPs and ultimately may become a therapeutic modality for GBM.
Diffuse Midline Gliomas with Histone 3-Lysine-27-Methionine (H3K27M) mutation constitute the majority of Diffuse Intrinsic Pontine Glioma (DIPG), which is the most aggressive form of pediatric glioma ...with a dire prognosis. DIPG are lethal tumors found in younger children with a median survival <1 year from diagnosis. Discovery of the characteristic H3K27M mutations offers opportunity and hope for development of targeted therapies for this deadly disease. The H3K27M mutation, likely through epigenetic alterations in specific H3 lysine trimethylation levels and subsequent gene expression, plays a significant role in pathogenesis of DIPG. Animal models accurately depicting molecular characteristics of H3K27M DIPG are important to elucidate underlying pathologic events and for preclinical drug evaluation. Here we review the past and present DIPG models and describe our efforts developing patient derived cell lines and xenografts from pretreated surgical specimens. Pre-treated surgical samples retain the characteristic genomic and phenotypic hallmarks of DIPG and establish orthotopic tumors in the mouse brainstem that recapitulate radiographic and morphological features of the original human DIPG tumor. These models that contain the H3K27M mutation constitute a valuable tool to further study this devastating disease and ultimately may uncover novel therapeutic vulnerabilities.
Highlights • Cranioplasty is a common procedure that carries an abnormally high rate of infection. • The authors assessed the effect of various variables on the risk of infection. • Pre-operative ...degree of neurological disability was the strongest of all predictors. • Cranial trauma and autologous grafts were trends toward a higher risk for infection. • Careful patient selection is a key concept in avoiding harmful infections.
Abstract
Ultrasound in combination with the introduction of microbubbles into the vasculature effectively opens the blood brain barrier (BBB) to allow the passage of therapeutic agents. Increased ...permeability of the BBB is typically demonstrated with small-molecule agents (e.g., 1-nm gadolinium salts). Permeability to small-molecule agents, however, cannot reliably predict the transfer of remarkably larger molecules (e.g., monoclonal antibodies) required by numerous therapies. To overcome this issue, we developed a magnetic resonance imaging analysis based on the ΔR
2
* physical parameter that can be measured intraoperatively for efficient real-time treatment management. We demonstrate successful correlations between ΔR
2
* values and parenchymal concentrations of 3 differently sized (18 nm–44 nm) populations of liposomes in a rat model. Reaching an appropriate ΔR
2
* value during treatment can reflect the effective delivery of large therapeutic agents. This prediction power enables the achievement of desirable parenchymal drug concentrations, which is paramount to obtaining effective therapeutic outcomes.
Data from human biopsies,
and
models, strongly supports the role of thrombin, and its protease-activated receptor (PAR1) in the pathology and progression of glioblastoma (GBM), a high-grade glial ...tumor. Activation of PAR1 by thrombin stimulates vasogenic edema, tumor adhesion and tumor growth. We here present a novel six amino acid chloromethyl-ketone compound (SIXAC) which specifically inhibits PAR1 proteolytic activation and counteracts the over-activation of PAR1 by tumor generated thrombin. SIXAC effects were demonstrated
utilizing 3 cell-lines, including the highly malignant CNS-1 cell-line which was also used as a model for GBM
. The
effects of SIXAC on proliferation rate, invasion and thrombin activity were measured by XTT, wound healing, colony formation and fluorescent assays, respectively. The effect of SIXAC on GBM
was assessed by measuring tumor and edema size as quantified by MRI imaging, by survival follow-up and brain histopathology. SIXAC was found
to inhibit thrombin-activity generated by CNS-1 cells (IC
= 5 × 10
M) and significantly decrease proliferation rate (
< 0.03) invasion (
= 0.02) and colony formation (
= 0.03) of these cells. In the CNS-1 GBM rat animal model SIXAC was found to reduce edema volume ratio (8.8 ± 1.9 vs. 4.9 ± 1,
< 0.04) and increase median survival (16 vs. 18.5 days,
< 0.02 by Log rank Mental-Cox test). These results strengthen the important role of thrombin/PAR1 pathway in glioblastoma progression and suggest SIXAC as a novel therapeutic tool for this fatal disease.
Abstract
BACKGROUND
It is a well-established practice to perform brain-mapping scans of patients diagnosed with dominant frontal/temporal lesions to evaluate their language activation areas (LAAs) ...and pathways prior to surgical intervention. Dependent on the pathology, brain functional regions and their associated pathways may be exposed to post-operative radiation as part of the patient's treatment protocol. The post-radiation detrimental effect on cognition is well-known, however, the effect of surgical resection and subsequent radiation on LAAs and pathways' integrity is not well studied. Here, the impact of surgical resection and radiation on LAAs and pathways integrity is examined.
METHODS
8 patients that underwent surgical resection to frontal/temporal lesion located at their dominant hemisphere followed by radiation treatment with at least two brain-mapping scans in Sheba Medical Center between the years 2012 to 2021 were collected. Location of functional LAAs (such as Broca's and Wernicke’s areas) as well as that of structural fiber tracts (such as the arcuate fasciculus) were determined. Volumetric and tumor geometry data was measured and documented. Laterality index of activation and Fractional Anisotropy (FA) quantitative values were calculated and compared from the baseline scan to the post-treatments scan for each patient.
RESULTS
Patients’ demographics analysis showed that their median age-at-diagnosis was 41 years (range, 4-64). The median overall survival was 89 months (range, 19-130) and the median follow-up duration was 80 months (range, 16-129). Radiation mean dose was 57Gy (range 40.05-60) and Planning treatment volume was 315ml (range 123.3-456.5) Notably, the mean laterality index of LAAs was also affected by intervention (p=0.044). Additionally, the arcuate fasciculus’ FA values differed in the post-interventions scan compared to the pre-interventions scan
CONCLUSION
surgical resection and radiation treatment may cause changes in the lateralization of the LAAs that may represent an attempt to compensate for a significant brain injury.
Factor Xa (FXa) plays a critical role in the coagulation cascade by generation of thrombin. During focal ischemia thrombin levels increase in the brain tissue and cause neural damage. This study ...examined the hypothesis that administration of the FXa inhibitor, apixaban, following focal ischemic stroke may have therapeutic potential by decreasing brain thrombin activity and infarct volume. Male mice were divided into a treated groups that received different doses of apixaban (2, 20, 100 mg/kg administered I.P.) or saline (controls) immediately after blocking the middle cerebral artery (MCA). Thrombin activity was measured by a fluorescence assay on fresh coronal slices taken from the mice brains 24 hr following the MCA occlusion. Infarct volume was assessed using triphenyltetrazolium chloride staining. A high dose of apixaban (100 mg/kg) significantly decreased thrombin activity levels in the ipsilateral hemisphere compared to the control group (Slice#5, p = .016; Slice#6, p = .016; Slice#7, p = .016; Slice#8, p = .036; by the nonparametric Mann–Whitney test). In addition, treatment with apixaban doses of both 100 mg/kg (32 ± 8% vs. 76 ± 7% in the treatment vs. control groups respectively; p = .005 by the nonparametric Mann–Whitney test) and 20 mg/kg (43 ± 7% vs. 76 ± 7% in the treatment vs. control groups respectively; p = .019 by the nonparametric Mann–Whitney test) decreased infarct volumes in areas surrounding the ischemic core (Slices #3 and #8). No brain hemorrhages were observed either in the treated or control groups. In summary, I.P. administration of high dose of apixaban immediately after MCA occlusion decreases brain thrombin activity and reduces infarct size.
A definitive diagnosis of brain lesions not amenable to surgery is mainly made by stereotactic needle biopsy. The diagnostic yield and safety of the frameless versus frame-based image-guided ...stereotactic techniques is unclear. Our objective was to evaluate the safety and accuracy of frameless versus frame-based stereotactic brain biopsy techniques.
A total of 278 patients (153 men; mean age: 65.5 years) with intra-axial brain lesions underwent frame-based (n = 148) or frameless image-guided stereotactic brain biopsy (n = 130) using a minimally invasive twist drill technique during 2010–2016 at Sheba Medical Center. Demographic, imaging, and clinical data were retrospectively analyzed.
The diagnostic yield (>90%) did not differ significantly between groups. Overall morbidity (6.8% vs. 8.5%), incidence of permanent neurologic deficits (2.1% vs. 1.6%), mortality rate (0.7% vs. 0.8%), and postoperative computed tomography–detected asymptomatic (14.2% vs. 16.1%) and symptomatic (2.0% vs. 1.6%) bleeding also did not differ significantly between the frame-based and frameless cohorts, respectively. The diagnostic yield and complication rates related to the biopsy technique were not significantly associated with sex, age, entry angle to the skull and skull thickness, lesion location or depth, or radiologic characteristics. Diagnostic yield was significantly associated with the mean lesion volume. Smaller lesions were less diagnostic than larger lesions in both techniques (P = 0.043 frame-based and P = 0.048 frameless).
The frameless biopsy technique is as efficient as the frame-based brain biopsy technique with a low complication rate. Lesion volume was the only predictive factor of diagnostic yield. The minimally invasive twist drill technique is safe and efficient.
Abstract
BACKGROUND
Meningiomas are the most common primary CNS tumor in adults, with a median age at diagnosis of 65 years. Younger patients usually have a genetic background or history of prior ...radiation exposure. Population-level studies suggest 80-85% of meningiomas are WHO grade I (benign), 15-18% grade II (atypical), and 1-3% grade III (anaplastic). This case series describes a single center experience of meningiomas in patients under 40.
METHODS
We reviewed the Sheba Medical Center Neurosurgery and radiotherapy databases containing patients operated on for meningioma between 2011-2020. Digital medical records were retrieved, including pathology reports, surgical reports, clinical and radiological data, and use of radiotherapy or medical treatments.
RESULTS
Of 600 patients in the database, 47 patients under 40 (7.8%) were identified and 54 tumors were reviewed (five patients had multiple operation). 32 patients were female (68%) ; 2 were under 20 years old, 17 were age 20-30 and 28 were age 31-39 at first presentation. Seven patients had received prior radiation therapy for a childhood malignancy. 28 meningiomas were histology confirmed grade I (52%), 22 were grade II (41%), 2 were grade III (4%), and 2 (4%) were grade undetermined. 22 tumors were located in the skull base (41%) and 32 (59%) in the brain convexity. 16 skull base tumors were grade I, five were grade II, and one was grade III. 12 convexity tumors were grade I, 16 were grade II, and two were grade III. Median follow-up was 35 months (range 1 - 98 months).
CONCLUSION
Our experience with meningioma patients under 40 revealed a different grade segregation than the older population, with younger patients showing a higher incidence of grade II tumors. These tumors are generally more aggressive, and require careful resection and consideration for post-surgical radiotherapy. Further validation with population based databases is required.
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