Molecular biological insights have led to a fundamental understanding of the underlying genomic mechanisms of nervous system disease. These findings have resulted in the identification of therapeutic ...genes that can be packaged in viral capsids for the treatment of a variety of neurological conditions, including neurodegenerative, metabolic, and enzyme deficiency disorders. Recent data have demonstrated that gene-carrying viral vectors (most often adeno-associated viruses) can be effectively distributed by convection-enhanced delivery (CED) in a safe, reliable, targeted, and homogeneous manner across the blood-brain barrier. Critically, these vectors can be monitored using real-time MRI of a co-infused surrogate tracer to accurately predict vector distribution and transgene expression at the perfused site. The unique properties of CED of adeno-associated virus vectors allow for cell-specific transgene manipulation of the infused anatomical site and/or widespread interconnected sites via antero- and/or retrograde transport. The authors review the convective properties of viral vectors, associated technology, and clinical applications.
Background and Aim: The benefit of stereotactic radiosurgery (SRS) in recurrent glioblastoma multiforme (GBM) remains unclear, partly due to disease heterogeneity. Subventricular zone (SVZ) invasion ...is a prognostic factor for primary GBM, but whether SVZ involvement is also prognostic in recurrent GBM treated with SRS is unknown. Here, we aimed to determine prognostic factors after first GBM recurrence. Materials and Methods: Thirty-nine consecutive patients with a first recurrence of glioblastoma treated at the Gamma Knife Center, Warsaw, Poland and the Franciszek Lukaszczyk Oncology Center, Bydgoszcz, Poland, between 2012 and 2016 were retrospectively reviewed. Magnetic resonance images were reviewed according to SVZ invasion by primary tumors and at the time of recurrence. Outcomes were evaluated using univariable and multivariable analyses. The study protocol was approved by the Ludwik Rydygier Collegium Medicum of Nicolas Copernicus University Institutional Review Board (approved No. KB 494/2018) on June 19, 2018. Results: SRS was the only prognostic factor for overall survival after recurrence in multivariable analysis. The median overall survival after the first recurrence was 18 months in the SRS group versus 6.5 months in the non-SRS group (P = 0.02). Survival after the first recurrence treated with SRS was shorter when recurrences were localized to the SVZ. Conclusion: SRS appears to be an effective salvage modality for small recurrent GBMs. Although SVZ-positive tumors have a worse prognosis, these tumors may benefit from SRS.
The objective of this study was to assess the feasibility, accuracy, effectiveness, and safety of an MRI-compatible frameless stereotactic ball-joint guide array (BJGA) as a platform for cannula ...placement and convection-enhanced delivery (CED).
The authors analyzed the clinical and imaging data from consecutive patients with aromatic l-amino acid decarboxylase (AADC) deficiency who underwent infusion of adeno-associated virus (AAV) containing the AADC gene (AAV2-AADC).
Eleven patients (7 females, 4 males) underwent bilateral MRI-guided BJGA cannula placement and CED of AAV2-AADC (22 brainstem infusions). The mean age at infusion was 10.5 ± 5.2 years (range 4-19 years). MRI allowed for accurate real-time planning, confirmed precise cannula placement after single-pass placement, and permitted on-the-fly adjustment. Overall, the mean bilateral depth to the target was 137.0 ± 5.2 mm (range 124.0-145.5 mm). The mean bilateral depth error was 0.9 ± 0.7 mm (range 0-2.2 mm), and the bilateral radial error was 0.9 ± 0.6 mm (range 0.1-2.3 mm). The bilateral absolute tip error was 1.4 ± 0.8 mm (range 0.4-3.0 mm). Target depth and absolute tip error were not correlated (Pearson product-moment correlation coefficient, r = 0.01).
Use of the BJGA is feasible, accurate, effective, and safe for cannula placement, infusion MRI monitoring, and cannula adjustment during CED. The low-profile universal applicability of the BJGA streamlines and facilitates MRI-guided CED.
One of the alternative methods of surgical treatment of vestibular schwannoma is Gamma Knife radiosurgery. The purpose of this metaanalysis was to analyze the progress in treatment of vestibular ...schwannoma using Gamma Knife radiosurgery based on data in the literature of the last five years.
In the collected English-language literature from the years 2007-2011, contained in 20 scientific journals, clinical articles of many years study at a single center were extracted and also review papers and case reports. The main criteria of our own analysis were: patient age, tumor size, the dose in Gy, the time from surgery to follow-up, the degree of tumor growth inhibition, and hearing preservation. For statistical calculations comparing series of studies we used nonparametric analysis of variance and tests at the significance level of p > 0.05.
The 46 evaluated clinical articles show the results of studies over many years. A comparison of the results of the analysis made on the basis of papers published in the period 1998-2007 with the results of the current series from the period 2007-2011 allowed us to establish that the average dose applied to the periphery of the tumor was lower (12.4 Gy) than in the earlier series of 1998-2007 (14.2 Gy), and hearing preservation was higher (66.45% vs. 51.0%).
Clinical findings widely documented in the literature over the past five years indicate the progress in treatment of vestibular schwannoma using Gamma Knife radiosurgery.
The current study compared the standard response assessment in neuro-oncology (RANO), immunotherapy RANO (iRANO), and modified RANO (mRANO) criteria as well as quantified the association between ...progression-free (PFS) and overall survival (OS) in an immunotherapy trial in recurrent glioblastoma (rGBM).
A total of 47 patients with rGBM were enrolled in a prospective phase II convection-enhanced delivery of an IL4R-targeted immunotoxin (MDNA55-05, NCT02858895). Bidirectional tumor measurements were created by local sites and centrally by an independent radiologic faculty, then standard RANO, iRANO, and mRANO criteria were applied.
A total of 41 of 47 patients (mean age 56 ± 11.7) were evaluable for response. PFS was significantly shorter using standard RANO compared with iRANO (log-rank,
< 0.0001;
= 0.3) and mRANO (
< 0.0001;
= 0.3). In patients who died and had confirmed progression on standard RANO, no correlation was observed between PFS and OS (local,
= 0.47; central,
= 0.34). Using iRANO, a weak association was observed between confirmed PFS and OS via local site measurements (
= 0.017), but not central measurements (
= 0.18). A total of 24 of 41 patients (59%) were censored using iRANO and because they lacked confirmation of progression 3 months after initial progression. A strong correlation was observed between mRANO PFS and OS for both local (
= 0.66,
< 0.0001) and centrally determined reads (
= 0.57,
= 0.0007).
No correlation between radiographic PFS and OS was observed for standard RANO or iRANO, but a correlation was observed between PFS and OS using the mRANO criteria. Also, the iRANO criteria was difficult to implement due to need to confirm progression 3 months after initial progression, censoring more than half the patients.
Abstract
Background
MDNA55 is an interleukin 4 receptor (IL4R)-targeting toxin in development for recurrent GBM, a universally fatal disease. IL4R is overexpressed in GBM as well as cells of the ...tumor microenvironment. High expression of IL4R is associated with poor clinical outcomes.
Methods
MDNA55-05 is an open-label, single-arm phase IIb study of MDNA55 in recurrent GBM (rGBM) patients with an aggressive form of GBM (de novo GBM, IDH wild-type, and nonresectable at recurrence) on their 1st or 2nd recurrence. MDNA55 was administered intratumorally as a single dose treatment (dose range of 18 to 240 ug) using convection-enhanced delivery (CED) with up to 4 stereo-tactically placed catheters. It was co-infused with a contrast agent (Gd-DTPA, Magnevist®) to assess distribution in and around the tumor margins. The flow rate of each catheter did not exceed 10μL/min to ensure that the infusion duration did not exceed 48 h. The primary endpoint was mOS, with secondary endpoints determining the effects of IL4R status on mOS and PFS.
Results
MDNA55 showed an acceptable safety profile at doses up to 240 μg. In all evaluable patients (n = 44) mOS was 11.64 months (80% one-sided CI 8.62, 15.02) and OS-12 was 46%. A subgroup (n = 32) consisting of IL4R High and IL4R Low patients treated with high-dose MDNA55 (>180 ug) showed the best benefit with mOS of 15 months, OS-12 of 55%. Based on mRANO criteria, tumor control was observed in 81% (26/32), including those patients who exhibited pseudo-progression (15/26).
Conclusions
MDNA55 demonstrated tumor control and promising survival and may benefit rGBM patients when treated at high-dose irrespective of IL4R expression level.
Trial Registration: Clinicaltrials.gov NCT02858895.
This study evaluates the applicability of S100B levels, mean maximum velocity (
V
mean
) over time, pulsatility index (PI), intracranial pressure (ICP), and body temperature (
T
) for the prediction ...of the treatment of patients with traumatic brain injury (TBI). Sixty patients defined by the Glasgow Coma Scale score ≤ 8 were stratified using the Glasgow Coma Scale into 2 groups: favorable (FG: Glasgow Outcome Scale ≥ 4) and unfavorable (UG: Glasgow Outcome Scale < 4). The S100B concentration was at the time of hospital admission.
V
mean
was measured using transcranial Doppler. PI was derived from a transcranial Doppler examination.
T
was measured in the temporal artery. The differences in mean between FG and UG were tested using a bootstrap test of 10,000 repetitions with replacement. Changes in S100B,
V
mean
, PI, ICP, and
T
levels stratified by the group were calculated using the one-way aligned rank transform for nonparametric factorial analysis of variance. The reference ranges for the levels of S100B,
V
mean
, and PI were 0.05 to 0.23 µg/L, 30.8 to 73.17 cm/s, and 0.62 to 1.13, respectively. Both groups were defined by an increase in
V
mean
, a decrease in S100B, PI, and ICP levels; and a virtually constant
T
. The unfavorable outcome is defined by significantly higher levels of all parameters, except
T
. A favorable outcome is defined by S100B < 3 mg/L, PI < 2.86, ICP > 25 mm Hg, and
V
mean
> 40 cm/s. The relationships provided may serve as indicators of the results of the TBI treatment.
High‐grade gliomas are aggressive, deadly primary brain tumors. Median survival of patients with glioblastoma (GBM, WHO grade 4) is 14 months and <10% of patients survive 2 years. Despite improved ...surgical strategies and forceful radiotherapy and chemotherapy, the prognosis of GBM patients is poor and did not improve over decades. We performed targeted next‐generation sequencing with a custom panel of 664 cancer‐ and epigenetics‐related genes, and searched for somatic and germline variants in 180 gliomas of different WHO grades. Herein, we focus on 135 GBM IDH‐wild type samples. In parallel, mRNA sequencing was accomplished to detect transcriptomic abnormalities. We present the genomic alterations in high‐grade gliomas and the associated transcriptomic patterns. Computational analyses and biochemical assays showed the influence of TOP2A variants on enzyme activities. In 4/135 IDH‐wild type GBMs we found a novel, recurrent mutation in the TOP2A gene encoding topoisomerase 2A (allele frequency AF = 0.03, 4/135 samples). Biochemical assays with recombinant, wild type (WT) and variant proteins demonstrated stronger DNA binding and relaxation activity of the variant protein. GBM patients carrying the altered TOP2A had shorter overall survival (median OS 150 vs 500 days, P = .0018). In the GBMs with the TOP2A variant we found transcriptomic alterations consistent with splicing dysregulation. luA novel, recurrent TOP2A mutation, which was found exclusively in four GBMs, results in the TOP2A E948Q variant with altered DNA binding and relaxation activities. The deleterious TOP2A mutation resulting in transcription deregulation in GBMs may contribute to disease pathology.
What's new?
The prognosis of patients with glioblastoma (GBM) is poor and has not improved despite advances in treatment. Here, the authors identified genetic variants and transcription abnormalities in 135 GBM samples. They describe a novel variant of the TOP2A gene, present in four cases, that correlates with shorter survival. The mutated TOP2A protein showed stronger DNA binding and relaxation activity than the wild type protein. This mutation may contribute to the progression of the disease, and could be a viable target for new therapies.
Abstract
BACKGROUND
Bizaxofusp (MDNA55) is an IL4R-targeting toxin in development for recurrent (r)GBM, a universally fatal disease with mOS of 6-9 months. IL-4R is overexpressed in GBM and ...surrounding tumor microenvironment, with high expression associated with poor clinical outcome. Method: Efficacy and safety were evaluated in a single-arm, open-label, multi-center Ph2 study using convection-enhanced delivery of Bizaxofusp. The primary endpoint of mOS was compared to results from a blinded eligibility-matched external control arm (ECA). OS was defined as time from relapse to death/censor. IL-4R expression was determined by immunohistochemistry of available archival tumor tissues from both arms.
RESULTS
Bizaxofusp showed an acceptable safety profile at doses of up to 240 μg. Forty-four subjects were treated with Bizaxofusp per protocol; 81 ECA subjects met the eligibility criteria of the study. The Bizaxofusp group had a significantly longer mOS (12.85 months compared to 7.7 months for ECA; HR, 0.62; 95% CI, 0.42-0.89). Amongst the unmethylated MGMT and high IL-4R sub-groups, subjects treated with Bizaxofusp had significantly longer mOS when compared to the ECA. Eleven patients (25%) treated with Bizaxofusp survived >24 months; 3 patients were still alive (29.9, 32.8 and 40.1 months) at last follow-up. High IL-4R expression was associated with improved survival (mOS, 15.8 versus 9.8 months; HR, 0.7; 95% CI, 0.39-1.46) at all doses. However at high doses (180 μg) subjects with low IL-4R expression had significantly longer survival versus low dose Bizaxofusp (mOS, 15.4 versus 9.1 months; HR, 0.28; 95% CI, 0.09-0.91).
CONCLUSION
In patients with rGBM, a single treatment of Bizaxofusp resulted in significantly improved OS compared to eligibility-matched ECA. High-dose Bizaxofusp was equally effective irrespective of IL4R expression. A Phase 3 registration trial will use a novel hybrid design with a propensity-matched ECA comprising two-thirds of the control arm, setting a new precedent for GBM clinical trials.
Background:
Spontaneous intracranial hypotension (SIH) is a rare disease characterized by a decrease in the volume and pressure of cerebrospinal fluid (CSF) resulting from its leakage through the ...dura mater. SIH is curable, but it can lead to serious clinical sequelae or even death if not treated properly.
Case Description:
A 37-year-old female with headaches occurring in standing position and increasing especially during verticalization. Magnetic resonance imaging showed an image characteristic of SIH. Conservative treatment was applied in the form of bed rest. CT myelography scan located the site of CSF leakage. As the conservative treatment proved inefficient, it was decided to perform an epidural fistula sealing using the patient’s venous blood, administered under computed tomography guidance. The performed procedure completely resolved the patient’s complaints, allowing her to be discharged home.
Conclusion:
Patients with suspected SIH should remain in the supine position until a definitive diagnosis is made. Sealing the meningeal fistula with venous blood under computed tomography guidance should be considered in case of conservative treatment failure.
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