Captive Bolt Gun-Related Vascular Injury: A Single Center Experience.

This article investigates the clinical and radiological characteristics of captive bolt gun head injuries, a rare form of low-velocity penetrating brain injury. Eleven consecutive patients were included in the study. Vascular injuries and the rate of infection were systematically analyzed. Radiological findings reveal common bolt trajectories in the anterior cranial fossa, with identified risk factors for a poor outcome including trajectory crossing midline, hematocephalus, and paranasal sinus involvement. Only one patient had a good outcome. Despite meticulous microsurgical techniques, this study highlights often unfavorable clinical outcomes in captive bolt gun injuries, with vascular injury identified as a potential contributing risk factor for a poor outcome. Knowledge of variant vascular tree anatomy and corresponding vascular territory is important. To avoid potential vascular injuries, a complete removal of bone fragments was not always performed and it did not increase the rate of infection, challenging the conventional wisdom advocating for the complete removal of bone fragments. These findings contribute novel insights into captive bolt gun-related injuries, paving the way for further research.

Results of Surgical Treatment of Occult Spinal Dysraphisms-A Single Centre Experience.

Occult spinal dysraphisms (OSDs) are caused by various defects in the embryogenesis of the spinal cord and represent an obstacle to the ascent of the conus, which allows the conus to pass from the lower levels of the spinal canal to the final position between L1 and L2 during normal foetal life. When an OSD tethers the spinal cord at the lower levels, it can lead to neurological symptoms, better known as tethered cord syndrome. Surgical treatment of OSD is primarily aimed at untethering the spinal cord. In asymptomatic patients, this can protect against the long-term development of neurological deficits. In symptomatic patients, this can halt or limit the progression of existing symptoms. The aim of this study is to examine all paediatric and adult patients diagnosed with OSD and treated in the Department of Neurosurgery at the University Medical Centre Ljubljana during the 5-year period of 2016-2021. All patients diagnosed with OSD during this period were included in the study. Patient characteristics, treatment modalities and outcomes were studied with the aim of describing the differences between the paediatric and adult population and defining the rationality of treating these pathological conditions. We included in the study 52 patients with 64 occult dysraphic lesions. Adults (>18 years old) represented 15/52 (28.8%) of all patients, while 37/52 (71.8%) were children. The most common OSDs were conus lipomas, followed by dermal sinus tracts, filum terminale lipomas and split cord malformations. Surgical treatment was performed in 35/52 (67.3%) cases, while conservative management was chosen in 17/52 (32.6%) cases. The preoperative presence of symptoms was statistically higher in adults than in children (p = 0.0098). Surgery on complex spinal cord lipomas was statistically related to a higher rate of postoperative neurological complications (p = 0.0002). The treatment of OSD is complex and must be based on knowledge of the developmental anomalies of the spine and spinal cord. Successful surgical treatment relies on microsurgical techniques and the use of neuromonitoring. Successful treatment can prevent or limit the occurrence of neurological problems.

Anti-Vimentin Nanobody Decreases Glioblastoma Cell Invasion In Vitro and In Vivo.

PURPOSE: Glioblastoma (GBM) is the most common primary brain tumour and one of the deadliest cancers. In addition to late diagnosis and inadequate treatment, the extremely low survival rate is also due to the lack of appropriate therapeutic biomarkers and corresponding therapeutic agents. One of the potential therapeutic biomarkers is the intermediate filament vimentin, which is associated with epithelial-mesenchymal transition (EMT). The purpose of this study was to analyse the effect of the anti-vimentin nanobody Nb79 on cell invasion in vitro and in vivo. To further our understanding of the mechanism of action, we investigated the association between Nb79 and EMT in GBM and GBM stem cells by analysing the expression levels of key EMT-related proteins. METHODS: The expression of vimentin in glioma tissues and cells was determined by RT-qPCR. An invasion assay was performed on differentiated glioblastoma cell line U-87 MG and stem cell line NCH421k in vitro as well as in vivo in zebrafish embryos. The effect of Nb79 on expression of EMT biomarkers beta-catenin, vimentin, ZEB-1 and ZO1 was determined by Western blot and immunocytochemistry. RESULTS: Our study shows that vimentin is upregulated in glioblastoma tissue compared to lower grade glioma and non-tumour brain tissue. We demonstrated that treatment with Nb79 reduced glioblastoma cell invasion by up to 64% in vitro and up to 21% in vivo. In addition, we found that the tight junction protein ZO-1 had higher expression on the cell membrane, when treated with inhibitory anti-vimentin Nb79 compared to control. CONCLUSION: In conclusion, our results suggest that anti-vimentin nanobody Nb79 is a promising tool to target glioblastoma cell invasion.

The Cytotoxic Effects of Cannabidiol and Cannabigerol on Glioblastoma Stem Cells May Mostly Involve GPR55 and TRPV1 Signalling.

Glioblastoma (GBM) is one of the most aggressive cancers, comprising 60-70% of all gliomas. The large G-protein-coupled receptor family includes cannabinoid receptors CB1, CB2, GPR55, and non-specific ion receptor protein transporters TRPs. First, we found up-regulated CNR1, GPR55, and TRPV1 expression in glioma patient-derived tissue samples and cell lines compared with non-malignant brain samples. CNR1 and GPR55 did not correlate with glioma grade, whereas TRPV1 negatively correlated with grade and positively correlated with longer overall survival. This suggests a tumour-suppressor role of TRPV1. With respect to markers of GBM stem cells, preferred targets of therapy, TRPV1 and GPR55, but not CNR1, strongly correlated with different sets of stemness gene markers: NOTCH, OLIG2, CD9, TRIM28, and TUFM and CD15, SOX2, OCT4, and ID1, respectively. This is in line with the higher expression of TRPV1 and GPR55 genes in GSCs compared with differentiated GBM cells. Second, in a panel of patient-derived GSCs, we found that CBG and CBD exhibited the highest cytotoxicity at a molar ratio of 3:1. We suggest that this mixture should be tested in experimental animals and clinical studies, in which currently used Δ9-tetrahydrocannabinol (THC) is replaced with efficient and non-psychoactive CBG in adjuvant standard-of-care therapy.

Development and Internal Validation of the ARISE Prediction Models for Rebleeding After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Aneurysmal rerupture is one of the most important determents for outcome after aneurysmal subarachnoid hemorrhage and still occurs frequently because individual risk assessment is challenging given the heterogeneity in patient characteristics and aneurysm morphology. OBJECTIVE: To develop and internally validate a practical prediction model to estimate the risk of aneurysmal rerupture before aneurysm closure. METHODS: We designed a multinational cohort study of 2 prospective hospital registries and 3 retrospective observational studies to predict the risk of computed tomography confirmed rebleeding within 24 and 72 hours after ictus. We assessed predictors with Cox proportional hazard regression analysis. RESULTS: Rerupture occurred in 269 of 2075 patients. The cumulative incidence equaled 7% and 11% at 24 and 72 hours, respectively. Our base model included hypertension, World Federation of Neurosurgical Societies scale, Fisher grade, aneurysm size, and cerebrospinal fluid drainage before aneurysm closure and showed good discrimination with an optimism corrected c-statistic of 0.77. When we extend the base model with aneurysm irregularity, the optimism-corrected c-statistic increased to 0.79. CONCLUSION: Our prediction models reliably estimate the risk of aneurysm rerupture after aneurysmal subarachnoid hemorrhage using predictor variables available upon hospital admission. An online prognostic calculator is accessible at https://www.evidencio.com/models/show/2626 .

Upregulation of Cathepsin X in Glioblastoma: Interplay with γ-Enolase and the Effects of Selective Cathepsin X Inhibitors.

Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults. Understanding GBM pathobiology and discovering novel therapeutic targets are critical to finding efficient treatments. Upregulation of the lysosomal cysteine carboxypeptidase cathepsin X has been linked to immune dysfunction and neurodegenerative diseases, but its role in cancer and particularly in GBM progression in patients is unknown. In this study, cathepsin X expression and activity were found to be upregulated in human GBM tissues compared to low-grade gliomas and nontumor brain tissues. Cathepsin X was localized in GBM cells as well as in tumor-associated macrophages and microglia. Subsequently, potent irreversible (AMS36) and reversible (Z7) selective cathepsin X inhibitors were tested in vitro. Selective cathepsin X inhibitors decreased the viability of patient-derived GBM cells as well as macrophages and microglia that were cultured in conditioned media of GBM cells. We next examined the expression pattern of neuron-specific enzyme γ-enolase, which is the target of cathepsin X. We found that there was a correlation between high proteolytic activity of cathepsin X and C-terminal cleavage of γ-enolase and that cathepsin X and γ-enolase were colocalized in GBM tissues, preferentially in GBM-associated macrophages and microglia. Taken together, our results on patient-derived material suggest that cathepsin X is involved in GBM progression and is a potential target for therapeutic approaches against GBM.

TRIM28 Selective Nanobody Reduces Glioblastoma Stem Cell Invasion.

Glioblastoma (GB), is the most common and aggressive malignant primary brain tumour in adults. Intra- and inter-tumour heterogeneity, infiltrative GB cell invasion and presence of therapy-resistant GB stem cells (GSCs) represent major obstacles to favourable prognosis and poor therapy response. Identifying the biomarkers of the most aggressive tumour cells and their more efficient targeting strategies are; therefore, crucial. Recently, transcription factor TRIM28 has been identified as a GB biomarker and, in this study, we have shown high expression of TRIM28 in GB and in low grade gliomas as well as higher expression in GSCs vs. differentiated GB cells, although in both cases not significant. We demonstrated significant in vitro inhibition of GB cells and GSCs invasiveness and spread in zebrafish brains in vivo by anti-TRIM28 selective nanobody NB237. TRIM28 was also enriched in GB (tumour) core and associated with the expression of stem cell genes, but was not prognostic for overall survival. However, based on the above results, we conclude that TRIM28 nanobody NB237 offers a new opportunity as a GB therapeutic tool.

Cystatin F acts as a mediator of immune suppression in glioblastoma.

PURPOSE: Glioblastoma, the most aggressive type of brain cancer, is composed of heterogeneous populations of differentiated cells, cancer stem cells and immune cells. Cystatin F, an endogenous inhibitor of lysosomal cysteine peptidases, regulates the function of cytotoxic immune cells. The aim of this study was to determine which type of cells expresses cystatin F in glioblastoma and to determine the role of cystatin F during disease progression. METHODS: RT-qPCR and immunohistochemistry were used to determine cystatin F mRNA and protein levels in glioblastoma tissue samples. The internalization of cystatin F was analyzed by Western blotting. Enzyme kinetics, real time invasion and calcein release cytotoxicity assays were used to assess the role of internalized cystatin F. RESULTS: We found that cystatin F was not expressed in non-cancer brain tissues, but that its expression increased with glioma progression. In tumor tissues, extensive staining was observed in cancer stem-like cells and microglia/monocytes, which secrete cystatin F into their microenvironment. In trans activity of cystatin F was confirmed using an in vitro glioblastoma cell model. Internalized cystatin F affected cathepsin L activity in glioblastoma cells and decreased their invasiveness. In addition, we found that cystatin F decreased the susceptibility of glioblastoma cells to the cytotoxic activity of natural killer (NK) cells. CONCLUSIONS: Our data implicate cystatin F as a mediator of immune suppression in glioblastoma. Increased cystatin F mRNA and protein levels in immune, glioblastoma and glioblastoma stem-like cells or trans internalized cystatin F may have an impact on decreased susceptibility of glioblastoma cells to NK cytotoxicity.

CCR5-Mediated Signaling Is Involved in Invasion of Glioblastoma Cells in Its Microenvironment.

The chemokine CCL5/RANTES is a versatile inflammatory mediator, which interacts with the receptor CCR5, promoting cancer cell interactions within the tumor microenvironment. Glioblastoma is a highly invasive tumor, in which CCL5 expression correlates with shorter patient survival. Using immunohistochemistry, we identified CCL5 and CCR5 in a series of glioblastoma samples and cells, including glioblastoma stem cells. CCL5 and CCR5 gene expression were significantly higher in a cohort of 38 glioblastoma samples, compared to low-grade glioma and non-cancerous tissues. The in vitro invasion of patients-derived primary glioblastoma cells and glioblastoma stem cells was dependent on CCL5-induced CCR5 signaling and is strongly inhibited by the small molecule CCR5 antagonist maraviroc. Invasion of these cells, which was enhanced when co-cultured with mesenchymal stem cells (MSCs), was inhibited by maraviroc, suggesting that MSCs release CCR5 ligands. In support of this model, we detected CCL5 and CCR5 in MSC monocultures and glioblastoma-associated MSC in tissue sections. We also found CCR5 expressing macrophages were in close proximity to glioblastoma cells. In conclusion, autocrine and paracrine cross-talk in glioblastoma and, in particular, glioblastoma stem cells with its stromal microenvironment, involves CCR5 and CCL5, contributing to glioblastoma invasion, suggesting the CCL5/CCR5 axis as a potential therapeutic target that can be targeted with repositioned drug maraviroc.

TRANS-ENDOSCOPIC TREATMENT OF CRANIOPHARYNGIOMA AND RECOVERY FROM BLINDNESS IN ADULT PATIENT - A CASE REPORT.

We report a case of trans-endoscopic transventricular approach to a large cystic craniopharyngioma. Surgery was performed three days after visual acuity on both eyes deteriorated to blindness. Magnetic resonance imaging before surgery revealed a large lesion in the suprasellar region that severely compressed the optic chiasm and displaced the third ventricle upward. The lesion was operated through the trans-endoscopic transventricular approach, with the aim of urgent decompression of the optic apparatus. At first, wide ventriculo-cysto-cisternostomy was performed, and then tumor tissue was removed. Postoperatively, visual acuity significantly improved on one eye. Our case shows that this minimally invasive technique is safe and effective and can be an alternative treatment for large cystic craniopharyngiomas. The reported case also shows that loss of vision can still be recovered even after the 72-hour period in adults.

Continuous Dynamic Mapping of the Corticospinal Tract in Motor Eloquent Tumor Surgery: Our Experience and Evaluation of the Method.

OBJECTIVE: The aim of this article is to present our experience with continuous dynamic mapping (CDM) of the corticospinal tract (CST) when removing tumors in motor eloquent regions. METHODS: We studied 44 patients with a brain tumor adjacent to the CST where CDM was used. The mapping probe was integrated at the tip of the suction device. Thresholds for eliciting MEPs were recorded. In all patients, along with CDM, MEPs to direct cortical stimulation were also monitored throughout the operation. Motor function was assessed preoperatively, after the procedure and on discharge. RESULTS: In the series, there were 37 patients with gliomas, six with brain metastasis, and one with cavernoma. The threshold to elicit MEPs in CDM was >20 mA in 17 cases, 16-20 mA in six cases, 11-15 mA in six cases, 6-10 mA in nine cases and 2-5 mA in six cases. MEPs to direct cortical stimulation were preserved in all patients. In three cases a new temporary motor deficit was noted. No new permanent motor deficit occurred. Gross total resection was reached in 57% of cases. CONCLUSIONS: From our experience, the combined use of CDM and MEPs to direct cortical stimulation improves the safety of surgery in the proximity of the CST, and at the same time offers the possibility of higher rates of gross total resection.

Concurrent intradural meningioma and schwannoma at the same lumbar level in a patient without neurofibromatosis: a case report.

Spinal schwannomas coexisting with meningiomas in patient without neurofibromatosis are extremely rare lesions. Here we present a case of 59-year-old patient with concurrent spinal meningioma and schwannoma at L1-L2 spinal level. This is the first case of the concurrent intradural tumours at the same lumbar level.

Localization patterns of cathepsins K and X and their predictive value in glioblastoma.

Background Glioblastoma is a highly aggressive central nervous system neoplasm characterized by extensive infiltration of malignant cells into brain parenchyma, thus preventing complete tumor eradication. Cysteine cathepsins B, S, L and K are involved in cancer progression and are overexpressed in glioblastoma. We report here for the first time that cathepsin X mRNA and protein are also abundantly present in malignant glioma. Materials and methods Gene expression of cathepsins K and X was analyzed using publically-available tran-scriptomic datasets and correlated with glioma grade and glioblastoma subtype. Kaplan-Maier survival analysis was performed to evaluate the predictive value of cathepsin K and X mRNA expression. Cathepsin protein expression was localized and semi-quantified in tumor tissues by immunohistochemistry. Results Highest gene expression of cathepsins K and X was found in glioblastoma, in particular in the mesenchymal subtype. Overall, high mRNA expression of cathepsin X, but not that of cathepsin K, correlated with poor patients' survival. Cathepsin K and X proteins were abundantly and heterogeneously expressed in glioblastoma tissue. Immuno-labeling of cathepsins K and X was observed in areas of CD133-positive glioblastoma stem cells, localized around arterioles in their niches that also expressed SDF-1α and CD68. mRNA levels of both cathepsins K and X correlated with mRNA levels of markers of glioblastoma stem cells and their niches. Conclusions The presence of both cathepsins in glioblastoma stem cell niche regions indicates their possible role in regulation of glioblastoma stem cell homing in their niches. The clinical relevance of this data needs to be elaborated in further prospective studies.

Analysis of Glioblastoma Patients' Plasma Revealed the Presence of MicroRNAs with a Prognostic Impact on Survival and Those of Viral Origin.

BACKGROUND: Glioblastoma multiforme (GBM) is among the most aggressive cancers with a poor prognosis in spite of a plethora of established diagnostic and prognostic biomarkers and treatment modalities. Therefore, the current goal is the detection of novel biomarkers, possibly detectable in the blood of GBM patients that may enable an early diagnosis and are potential therapeutic targets, leading to more efficient interventions. EXPERIMENTAL PROCEDURES: MicroRNA profiling of 734 human and human-associated viral miRNAs was performed on blood plasma samples from 16 healthy individuals and 16 patients with GBM, using the nCounter miRNA Expression Assay Kits. RESULTS: We identified 19 miRNAs with significantly different plasma levels in GBM patients, compared to the healthy individuals group with the difference limited by a factor of 2. Additionally, 11 viral miRNAs were found differentially expressed in plasma of GBM patients and 24 miRNA levels significantly correlated with the patients' survival. Moreover, the overlap between the group of candidate miRNAs for diagnostic biomarkers and the group of miRNAs associated with survival, consisted of ten miRNAs, showing both diagnostic and prognostic potential. Among them, hsa miR 592 and hsa miR 514a 3p have not been previously described in GBM and represent novel candidates for selective biomarkers. The possible signalling, induced by the revealed miRNAs is discussed, including those of viral origin, and in particular those related to the impaired immune response in the progression of GBM. CONCLUSION: The GBM burden is reflected in the alteration of the plasma miRNAs pattern, including viral miRNAs, representing the potential for future clinical application. Therefore proposed biomarker candidate miRNAs should be validated in a larger study of an independent cohort of patients.

Endoscopic treatment of in utero diagnosed multiloculated interhemispheric cyst in a newborn: case report.

Interhemispheric cysts, often associated with agenesis of corpus callosum, are rare lesions. The optimal treatment is still controversial. Placement of cystoperitoneal shunt and open microsurgery are traditional treatments. Neuroendoscopy in children is due to its minimal invasiveness a new emerging option. There have been a few published cases on neuroendoscopic treatment of interhemispheric cyst in children. The authors document the youngest reported child with multiloculated interhemispheric cyst that was treated with neuroendoscopy. The cyst was detected in a male fetus in 35th week of gestation and in utero magnetic resonance imaging was performed in 37th week of gestation. After delivery, progressive macrocrania with signs of raised intracranial pressure developed. Endoscopic cystoventriculocisternostomy was performed 28 days after the birth. There was a marked symptom relief. One month after the surgery, magnetic resonance showed shrinkage of the cyst and expansion of the brain parenchyma. After a 2-month follow up period, the child showed normal neurologic development and head circumference increased by only 0.5 cm. The created fenestrations enabled the brain to expand. Neuroendoscopic treatment,of interhemispheric cysts should be considered the operative technique of choice in newborns. Although the intracranial pressure and the size of the cyst have decreased, long-term follow up is necessary and future studies on more cases are needed.