Intracranial Growth Research Articles

Impact of Morphological Factors on the Future Growth of Unruptured Posterior Communicating Artery Aneurysms

No previous study has established the factors associated with intracranial aneurysm growth using imaging data obtained before the appearance of morphological changes. Therefore, we investigated the factors related to future aneurysm growth in posterior communicating artery (Pcom) aneurysms. Using a longitudinal database of intracranial aneurysm cases, we reviewed the findings for consecutive patients with unruptured Pcom aneurysms admitted to our institute from 2012 to 2021. Magnetic resonance images obtained over time were used to evaluate aneurysm growth. Aneurysms showing growth over time (group G) and unchanged aneurysms (group U) were compared in terms of background data and morphological factors. 93 Pcom aneurysms (group G: 25 aneurysms, 25%; group U: 68 aneurysms, 75%) were eligible for the present study. Six aneurysm rupture events occurred in group G (24%). Among morphological factors, Pcom diameter (1.2±0.3mm vs. 0.8±0.7mm, P<0.01), bleb formation (group G: 39% vs. group U: 10%; odds ratio, 5.6; P=0.01), and the lateral projection of the dome (group G: 52% vs. group U: 13%; odds ratio, 3.2; P=0.023) were significantly different between the 2 groups. The sensitivity and specificity of a cutoff Pcom diameter of 0.73mm for predicting enlargement were 96% and 53%, respectively. Pcom diameter, bleb formation, and lateral dome projection were associated with growth of Pcom aneurysms. Aneurysms with these risk factors require careful follow-up imaging, which may facilitate early detection of aneurysm growth and prevention of rupture through therapeutic interventions.

Morpho-radiological and brain endocast analysis in the study of Hyperostosis Frontalis Interna (HFI): A combined approach.

The purpose of this study is to anatomically evaluate the impact on the patient intra vitam of an endocranial condition on a late 20th century skull housed in the Section of Legal Medicine of the University of Foggia (Foggia, Apulia, Italy). After performing a retrospective diagnosis, the condition is framed in the broader context of studies on this pathology. An anthropological and radiological analysis (X-ray and CT scan imaging) made it possible to confirm the preliminary information and to detail the osteological diagnosis of HFI. In order to assess the impact on the cerebral surface of the endocranial growth a 3D endocast was obtained using the Software OrtogOnBlender. The skull is demonstrated to have belonged to a female senile individual known, from limited documentary evidence, to have suffered from a psychiatric condition during her life. The final diagnosis is hyperostosis frontalis interna (HFI), Type D. Although a direct correlation between the demonstrated intracranial bony growth and the onset of the patient's psychiatric condition is difficult to retrospectively ascertain, the pressure exerted on this female individual's frontal lobe may have contributed to further degenerative behavioural changes in the last years of her life. This case adds to previous knowledge, especially from the palaeopathological literature, on this condition and, for the first time, presents a neuroanatomical approach to assess the global impact of the disease.

Association of elevated neutrophil-to-lymphocyte ratio with increased intracranial aneurysm stability scores and aneurysm growth

Background and purposeInflammation involves in the progression of intracranial aneurysms (IAs). However, whether the neutrophil-to-lymphocyte ratio (NLR) as an inflammatory marker links to IAs stability is unidentified. This study was performed to assess the association of the NLR with IAs stability. MethodsWe retrospectively reviewed the medical records of patients diagnosed with unruptured IAs from January 2014 to June 2018. According to the quartiles of the NLR, patients with unruptured IAs were categorized into four groups. We evaluated the association between the NLR and IAs stability scores and IAs growth. Multiple logistic regression models were used in the analysis. ResultsA significant dose-response association was found between the NLR with IAs stability scores and IAs growth. After adjustment for potential confounders, an elevated NLR (fourth quartile) was associated with increased PHASES score (>5) (adjusted odds ratio [OR], 2.007; 95% confidence interval [CI], 1.361–2.960; p<0.001 [p for trend <0.001]), increased ELAPSS score (>15) (adjusted OR, 1.581; 95% CI, 1.074–2.328; p=0.020 [p for trend =0.001]), increased JAPAN 3-year rupture risk score (>5) (adjusted OR, 1.512; 95% CI, 1.033–2.215; p=0.034 [p for trend <0.001]), and IAs growth (adjusted OR, 16.759; 95% CI, 3.022–92.928; p=0.001 [p for trend <0.001]). ConclusionAn elevated NLR was associated with increased IAs stability scores and IAs growth. The association between NLR and IAs stability need further investigate.

RNA Expression Signatures of Intracranial Aneurysm Growth Trajectory Identified in Circulating Whole Blood.

After detection, identifying which intracranial aneurysms (IAs) will rupture is imperative. We hypothesized that RNA expression in circulating blood reflects IA growth rate as a surrogate of instability and rupture risk. To this end, we performed RNA sequencing on 66 blood samples from IA patients, for which we also calculated the predicted aneurysm trajectory (PAT), a metric quantifying an IA's future growth rate. We dichotomized dataset using the median PAT score into IAs that were either more stable and more likely to grow quickly. The dataset was then randomly divided into training (n = 46) and testing cohorts (n = 20). In training, differentially expressed protein-coding genes were identified as those with expression (TPM > 0.5) in at least 50% of the samples, a q-value < 0.05 (based on modified F-statistics with Benjamini-Hochberg correction), and an absolute fold-change ≥ 1.5. Ingenuity Pathway Analysis was used to construct networks of gene associations and to perform ontology term enrichment analysis. The MATLAB Classification Learner was then employed to assess modeling capability of the differentially expressed genes, using a 5-fold cross validation in training. Finally, the model was applied to the withheld, independent testing cohort (n = 20) to assess its predictive ability. In all, we examined transcriptomes of 66 IA patients, of which 33 IAs were "growing" (PAT ≥ 4.6) and 33 were more "stable". After dividing dataset into training and testing, we identified 39 genes in training as differentially expressed (11 with decreased expression in "growing" and 28 with increased expression). Model genes largely reflected organismal injury and abnormalities and cell to cell signaling and interaction. Preliminary modeling using a subspace discriminant ensemble model achieved a training AUC of 0.85 and a testing AUC of 0.86. In conclusion, transcriptomic expression in circulating blood indeed can distinguish "growing" and "stable" IA cases. The predictive model constructed from these differentially expressed genes could be used to assess IA stability and rupture potential.

Investigation of the antioxidant status and the number of double-stranded DNA breaks in models of brain tumor lesion by metastases of non-small cell lung cancer in vivo

Purpose of the study. Evaluation of the antioxidant status and DNA damage in tissues of subcutaneous xenografts of non-small cell lung cancer and in peritumoral tissues created using the A549 and H1299 cell cultures.Materials and methods. The study included 35 intact male Balb/c Nude immunodeficient mice. Cell lines A549 and H1299 were used as transplantable tumor biomaterial. A CDX model was created in accordance with the protocol for supratentorial injections (Ozawa T., James C. D., 2010) adapted for this experiment. Growth rates were controlled and intracranial xenografts were visualized using a high-resolution micro-CT system. The activity of catalase and superoxide dismutase was determined with non-denaturing electrophoresis in 8 % and 12 % polyacrylamide gel. The concentrations of sulfhydryl groups were determined according to Ellman. The DNA damage in lymphocytes was determined by the comet assay.Results. The experiment resulted in the creation of models of brain tumors characterized by intracranial growth pattern in 100 %. The activity of catalase in the studied lysates of intracranial xenografts, peritumoral tissue and healthy tissues of tumor-bearing animals in all experimental groups increased statistically significantly relative to the healthy tissue of intact animals, and the greatest differences from the control were recorded in the group of animals with implanted H1299 culture at a concentration of 1 × 106 . Superoxide dismutase activity in the studied lysates of intracranial xenografts and peritumoral tissues statistically significantly increased compared to the control sample in all experimental groups. The highest increase in the SOD activity was observed in the tissues of intracranial xenografts with the highest tumor load, which amounted to 28.8 % and 32.9 % of the changes relative to the control sample. A statistically significant increase in the concentration of SH-groups relative to the control sample in tumor tissue lysates was revealed in all experimental groups, and the highest concentration (36.2 ± 0.47) was observed in the group of experimental animals with the highest tumor load. Percentage change in tail moment (DNA damage indicator) in groups O1, O2, O3 and O4 increased statistically significantly compared to the control sample by 55.8 %, 111.8 %, 97.3 % and 170 %, respectively.Conclusions. The observed increase in the activity of the antioxidant defense system, accumulation of oxidative modifications of proteins, and an increase in DNA double-strand breaks in the tissues of intracranial xenografts of non-small cell lung cancer in vivo suggest that the created models reflect processes similar to those in tumors of human non-small cell lung cancer.

ADAMTS1 as potential prognostic biomarker promotes malignant invasion of glioma.

Glioma is the most common intracranial malignancy in adults with a high degree of malignancy and poor prognosis, which is largely attributed to the existence of glioma stem cells (GSCs). Previous evidence indicated that the matrix metalloproteinase ADAMTS1 was implicated in the process of tumor invasion, but the involvement of ADAMTS1 in glioma malignant invasion remains poorly understood. The expression and prognosis values of ADAMTS1 were investigated in patients with glioma based on ONCOMINE and GEPIA databases. ADAMTS1 expression of different malignancy grade tissues was determined by immunohistochemistry. The effects of ADAMTS1 on cell proliferation and invasion were determined by clone formation assay and Transwell migration assay. The animal experiment was performed in an intracranial orthotopic xenograft model by knockout of ADAMTS1. Stemness properties and Notch1-SOX2 pathway were examined in stable ADAMTS1 knockdown GSCs. The expression levels of ADAMTS1 were significantly higher in glioma tissues and significantly correlated with the grade of malignancy and prognosis of glioma. Elevated ADAMTS1 expression was associated with SOX2, N-cadherin and the resistanceofchemoradiotherapy of glioma patients. ADAMTS1 knockout suppressed the intracranial orthotopic xenograft growth and prolonged the survival of xenograft mice in vivo. Mechanistically, we found a blockade of the migration and invasiveness of GSCs and the expression levels of Notch1 and SOX2 in absence of ADAMTS1. As a biomarker for prediction of prognosis, ADAMTS1 may affect the invasive phenotype of GSCs by regulating Notch1-SOX2 signaling pathway, thereby promoting the invasive growth of glioma.

Experience of using benralizumab in the treatment of patients with severe asthma in the clinical practice of pulmonologists in Saint-Petersburg

The accumulation of clinical experience in the use of biologic therapy in patients with severe bronchial asthma (SBA) in real-world clinical practice with the possible identification of additional, previously undescribed clinical outcomes is of practical interest.The aim. To present the results of an observational study of using benralizumab in SBA in real clinical practice of pulmonologists in Saint-Petersburg.Methods. We present the results of more than 1 year of follow-up of 18 patients with eosinophilic SBA (12 women, 6 men, age from 28 to 74, average age 55.0 ± 11.9 years). The patients received benralizumab in addition to standard treatment. Clinical, laboratory, and functional examination of the patients were performed, the frequency of exacerbations and additional clinical effects were assessed. Results. It has been shown that the inclusion of benralizumab in complex therapy resulted in a significant improvement in disease control, improved bronchial conduction, a significant decrease in blood eosinophilia, and a reduction in the number of exacerbations. A clinical example is given that indicates a stabilizing effect of this therapy on the course of recurrent nasal polyposis with an initially aggressive course (intracranial polyp growth).Conclusion. The possibility of significant improvement in the control of SBA with the use of biological therapy has been confirmed in real clinical practice. At the same time, data have been obtained that will allow expanding the indications for the use of benralizumab in the future.

Spotlight on the August 30 Issue

![Graphic][1]</img>#### Notable in Neurology This Week This issue features an article that examines the association between sex, menopause, and white matter hyperintensities; another determines optimal surveillance strategies for unruptured intracranial aneurysm growth. A featured article examines the association of healthy lifestyles with risk of Alzheimer disease and related dementias in low-income Black and White Americans. ### Quantitative Muscle Analysis in FSHD Using Whole-Body Fat-Referenced MRI: Composite Scores for Longitudinal and Cross-sectional Analysis This prospective, observational, multicenter study in patients with facioscapulohumeral muscular dystrophy (FSHD) type 1 demonstrated … [1]: /embed/inline-graphic-1.gif

Flow residence time in intracranial aneurysms evaluated by in vitro 4D flow MRI

The process of an intracranial aneurysm development, growth, and rupture is multifaceted and complex. In addition, clinical observations have identified the potential of thrombus formation within such aneurysms. While the underlying mechanism is not fully understood, the thrombi represent a potential risk factor for ischemic stroke. Emerging studies indicate that blood residence time (RT) is a promising hemodynamic metric associated with the aneurysm rupture and formation of intra-aneurysmal thrombi. Here, we present a methodology to experimentally evaluate both trajectory-wise and local RT based on magnetic resonance imaging (MRI) velocimetry, and apply it to in vitro flow measurements in scaled-up replicas of 9 patient-specific intracranial aneurysms. Lagrangian tracks of massless tracers are integrated from the velocity fields and averaged to return the mean RT in the aneurysm sac. This is found to be closely approximated by a simple time scale based on the sac diameter and space–time average of the aneurysmal fluid velocity. The mean RT is also correlated with the inflow time scale at the parent artery. These results also provide a basis for the estimation of RT when high-resolution hemodynamic maps are not available. With the continuous increase in accuracy and resolution enabled by progress in MRI technology, the methodology described here may in the future be applicable to in vivo data.

The Role of Hemodynamics through the Circle of Willis in the Development of Intracranial Aneurysm: A Systematic Review of Numerical Models.

Background: The role of regional hemodynamics in the intracranial aneurysmal formation, growth, and rupture has been widely discussed based on numerical models over the past decades. Variation of the circle of Willis (CoW), which results in hemodynamic changes, is associated with the aneurysmal formation and rupture. However, such correlation has not been further clarified yet. The aim of this systematic review is to investigate whether simulated hemodynamic indices of the CoW are relevant to the formation, growth, or rupture of intracranial aneurysm. Methods: We conducted a review of MEDLINE, Web of Science, and EMBASE for studies on the correlation between hemodynamics indices of the CoW derived from numerical models and intracranial aneurysm up to December 2020 in compliance with PRISMA guidelines. Results: Three case reports out of 1046 publications met our inclusion and exclusion criteria, reporting 13 aneurysms in six patients. Eleven aneurysms were unruptured, and the state of the other two aneurysms was unknown. Wall shear stress, oscillatory shear index, von-Mises tension, flow velocity, and flow rate were reported as hemodynamic indices. Due to limited cases and significant heterogeneity between study settings, meta-analysis could not be performed. Conclusion: Numerical models can provide comprehensive information on the cerebral blood flow as well as local flow characteristics in the intracranial aneurysm. Based on only three case reports, no firm conclusion can be drawn regarding the correlation between hemodynamic parameters in the CoW derived from numerical models and aneurysmal formation or rupture. Due to the inherent nature of numerical models, more sensitive analysis and rigorous validations are required to determine its measurement error and thus extend their application into clinical practice for personalized management. Prospero registration number: CRD42021125169.

P.167 Documented growth of a de novo intracranial capillary hemangioma: a case report

Background: Intracranial capillary hemangiomas are rare, particularly in adults, and diagnosis can be challenging. The literature lacks visualization of intracranial capillary hemangioma growth over time. Here we document growth of a de novo intracranial capillary hemangioma, initially interpreted radiologically as a glioma. Methods: We report a case of a 64 year old male with history of HIV, recent Lyme disease and unconfirmed prior COVID-19 infection, who presented with exhaustion and confusion. Imaging demonstrated an intra-axial high T2/FLAIR signal lesion centred in the subcortical white matter of the posterior right temporal lobe. There was faint enhancement, and a few mildly prominent vessels were seen along its anterior aspect. Imaging 2 years prior had not shown the lesion. Stereotactic biopsy was nondiagnostic. Craniotomy and resection was carried out. Results: Pathological examination and immunohistochemistry returned the diagnosis of capillary hemangioma. We review how this case adds to proposed theories of de novo intracranial capillary hemangioma growth. Our patient’s co-morbidities support possible inflammation related triggers for symptomatic progression of these uncommon lesions. Conclusions: This unusual case documents the radiological appearance and progression of a de novo intracranial capillary hemangioma. It represents the first time such growth has been visualized in an adult male.

Hemodynamic changes after intracranial aneurysm growth.

For accurate risk assessment of unruptured intracranial aneurysms, it is important to understand the underlying mechanisms that lead to rupture. It is known that hemodynamic anomalies contribute to aneurysm growth and rupture, and that growing aneurysms carry higher rupture risks. However, it is unknown how growth affects hemodynamic characteristics. In this study, the authors assessed how hemodynamic characteristics change over the course of aneurysm growth. The authors included patients with observed aneurysm growth on longitudinal MRA in the period between 2012 and 2016. Patient-specific vascular models were created from baseline and follow-up images. Subsequently, intraaneurysmal hemodynamic characteristics were computed using computational fluid dynamics. The authors computed the normalized wall shear stress, oscillatory shear index, and low shear area to quantify hemodynamic characteristics. Differences between baseline and follow-up measurements were analyzed using paired t-tests. Twenty-five patients with a total of 31 aneurysms were included. The aneurysm volume increased by a median (IQR) of 26 (9-39) mm3 after a mean follow-up period of 4 (range 0.4-10.9) years. The median wall shear stress decreased significantly after growth. Other hemodynamic parameters did not change significantly, although large individual changes with large variability were observed. Hemodynamic characteristics change considerably after aneurysm growth. On average, wall shear stress values decrease after growth, but there is a large variability in hemodynamic changes between aneurysms.

Breast cancer extracellular vesicles-derived miR-1290 activates astrocytes in the brain metastatic microenvironment via the FOXA2→CNTF axis to promote progression of brain metastases

Mechanisms underlying breast cancer brain metastasis (BCBM) are still unclear. In this study, we observed that extracellular vesicles (EVs) secreted from breast cancer cells with increased expression of tGLI1, a BCBM-promoting transcription factor, strongly activated astrocytes. EV-derived microRNA/miRNA microarray revealed tGLI1-positive breast cancer cells highly secreted miR-1290 and miR-1246 encapsulated in EVs. Genetic knockin/knockout studies established a direct link between tGLI1 and both miRNAs. Datamining and analysis of patient samples revealed that BCBM patients had more circulating EV-miRs-1290/1246 than those without metastasis. Ectopic expression of miR-1290 or miR-1246 strongly activated astrocytes whereas their inhibitors abrogated the effect. Conditioned media from miR-1290- or miR-1246-overexpressing astrocytes promoted mammospheres. Furthermore, miRs-1290/1246 suppressed expression of FOXA2 transcription repressor, leading to CNTF cytokine secretion and subsequent activation of astrocytes. Finally, we conducted a mouse study to demonstrate that astrocytes overexpressing miR-1290, but not miR-1246, enhanced intracranial colonization and growth of breast cancer cells. Collectively, our findings demonstrate, for the first time, that breast cancer EV-derived miR-1290 and miR-1246 activate astrocytes in the brain metastatic microenvironment and that EV-derived miR-1290 promotes progression of brain metastases through the novel EV-miR-1290→FOXA2→CNTF signaling axis.

Retrospective Investigation of Cranial Volume and Cephalic Index in Patients with Nonsyndromic Sagittal Synostosis Operated by Total Vault Remodeling

Background: Premature fusion of cranial sutures affects skull development and leads to head deformity. Intracranial pressure increase and brain growth restriction can occur in untreated craniosynostosis. Operative treatment aims to achieve an immediate and long-lasting correction of skull shape that is close to the average and to prevent or release possible increased intracranial pressure by increasing the intracranial volume (ICV) or normalizing the ICV if it is already below the standards. This study was designed to evaluate the effect of a total calvarial reconstruction on skull development in patients with nonsyndromic sagittal synostosis. Material and Methods: The study population included 19 male and 5 female patients with isolated nonsyndromic sagittal suture synostosis. During the operation, temporarily fixed prebent metal plates provided an intraoperative reference for the desired cranial expansion gain of height and shortening. Preoperative and postoperative ICVs and cephalic indices were measured on computed tomography datasets using the software program ImageJ and were compared with one another and with normative data. Results: The male population presented with a preoperative mean ICV of 863.3 cm³. A postoperative mean ICV increase of 243.5 cm³ (p < 0.001) and a further ICV enlargement (p < 0.001) was measured. The mean CI changed from 71.0% preoperatively to 75.4% postoperatively (p = 0.002) and decreased insignificantly in the follow-up (p = 0.546). The female population had a preoperative mean ICV of 804.9 cm³. Postoperatively, the mean ICV increased by 211.1 cm³ (p = 0.043) and also increased in the follow-up (p = 0.043). Their mean CI values increased from 66.5% preoperatively to 72.8% (p = 0.043) postoperatively and decreased insignificantly in the follow-up (p = 0.345). Conclusion: This method of total vault remodeling provides reliable ICV increase and improvement in length and width of skull proportions beyond the immediate postoperative period together with an ICV increase.

Circumferential wall enhancement with contrast ratio measurement in unruptured intracranial aneurysm for aneurysm instability.

BackgroundAneurysm wall enhancement on high‐resolution vessel wall imaging (HR‐VWI) may represent vessel wall inflammation for unruptured intracranial aneurysms (UIAs). Further evidence for the role of circumferential aneurysm wall enhancement (CAWE) in evaluating the instability of UIAs is required, especially in small aneurysms (<7 mm).MethodsWe analyzed patients with saccular UIAs who prospectively underwent HR‐VWI on a 3.0 T MRI scanner in our center from September 2017 to August 2021. The presence of AWE was identified and quantitatively measured using the aneurysm‐to‐pituitary stalk contrast ratio (CRstalk) with maximal signal intensity value. The PHASES and ELAPSS scores were used to assess the risk of aneurysm rupture and growth. We evaluated the association of CAWE and CRstalk value with intracranial aneurysm instability.ResultsOne hundred patients with 109 saccular UIAs were included in this study. Eighty‐three UIAs (76.1%) had a size smaller than 7 mm. PHASES and ELAPSS scores were significantly higher in UIAs with CAWE than in UIAs without CAWE (p < .01). The association of CAWE with PHASES and ELAPSS scores remained in small UIAs (<7 mm). The optimal cutoff value of CRstalk for CAWE was 0.5. PHASES and ELAPSS scores were significantly higher in UIAs with CRstalk ≥0.5 than in UIAs with CRstalk <0.5 (p < .01).ConclusionsCAWE on HR‐VWI is a valuable imaging marker for aneurysm instability in UIAs. CRstalk value ≥0.5 may be associated with a higher risk of intracranial aneurysm rupture and growth.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Relationship between 3D Morphologic Change and 2D and 3D Growth of Unruptured Intracranial Aneurysms.

Untreated unruptured intracranial aneurysms are usually followed radiologically to detect aneurysm growth, which is associated with increased rupture risk. The ideal aneurysm size cutoff for defining growth remains unclear and also whether change in morphology should be part of the definition. We investigated the relationship between change in aneurysm size and 3D quantified morphologic changes during follow-up. We performed 3D morphology measurements of unruptured intracranial aneurysms on baseline and follow-up TOF-MRAs. Morphology measurements included surface area, compactness, elongation, flatness, sphericity, shape index, and curvedness. We investigated the relation between morphologic change between baseline and follow-up scans and unruptured intracranial aneurysm growth, with 2D and 3D growth defined as a continuous variable (correlation statistics) and a categoric variable (t test statistics). Categoric growth was defined as ≥1-mm increase in 2D length or width. We assessed unruptured intracranial aneurysms that changed in morphology and the proportion of growing and nongrowing unruptured intracranial aneurysms with statistically significant morphologic change. We included 113 patients with 127 unruptured intracranial aneurysms. Continuous growth of unruptured intracranial aneurysms was related to an increase in surface area and flatness and a decrease in the shape index and curvedness. In 15 growing unruptured intracranial aneurysms (12%), curvedness changed significantly compared with nongrowing unruptured intracranial aneurysms. Of the 112 nongrowing unruptured intracranial aneurysms, 10 (9%) changed significantly in morphology (flatness, shape index, and curvedness). Growing unruptured intracranial aneurysms show morphologic change. However, nearly 10% of nongrowing unruptured intracranial aneurysms change in morphology, suggesting that they could be unstable. Future studies should investigate the best growth definition including morphologic change and size to predict aneurysm rupture.

Efficacy and Safety of Tranexamic Acid Administration in Patients with Acute Traumatic Brain Injury: A Review of Current Literature

Hypothesis: Early administration of tranexamic acid (TXA) reduces mortality in patients suffering from acute traumatic brain injury (TBI). Methods: A structured search of PubMed and CENTRAL from inception until July 1st, 2022 was carried out seeking RCTs comparing the effects of TXA administration to placebo in patients suffering from TBI. The primary outcome tested was 28-day all-cause mortality. Secondary outcomes included intracranial hemorrhage growth and thromboembolic events. Results: Eight RCTs involving a total of 14,714 patients met the inclusion criteria; 7573 patients received TXA while 7141 patients received a placebo. There were 1415 patient deaths (18.7%) in the TXA group and 1410 patient deaths (19.7%) in the placebo group. None of the included studies reported a significant reduction in 28-day all-cause mortality, however, they all shared positive trends toward superior outcomes in the intervention arms. Two of the included studies reported significant reductions in intracranial hemorrhage expansion in those patients treated with TXA, with four more studies reporting trends toward superior outcomes in the TXA groups. There was no evidence of increased incidence of thromboembolic events in the TXA groups in four of the five studies that reported relevant data, with one study representing 1.2% of total patients reporting an increased incidence of pulmonary emboli in the intervention group. Conclusions: In patients suffering from acute TBI, early administration of TXA reduces intracranial hemorrhage growth and may have positive effects on mortality with no corresponding increase in thromboembolic events. Given these results, early administration of TXA in patients experiencing TBI is recommended in initial care. Keywords: Tranexamic acid, Traumatic brain injury, Intracranial hemorrhage, Mortality, Disability

TIMM44 is a potential therapeutic target of human glioma.

TIMM44 (translocase of inner mitochondrial membrane 44) is essential for the maintenance of mitochondrial functions. Bioinformatics studies and results from the local high-grade glioma tissues showed that TIMM44 mRNA and protein levels are elevated in glioma, correlating with poor overall survival. Mitochondrial TIMM44 upregulation was also detected in patient-derived primary glioma cells and immortalized cell line. In primary and established glioma cells, TIMM44 depletion, using the lentiviral shRNA strategy or the CRISPR/Cas9 knockout (KO) method, robustly inhibited cell viability, proliferation and migration. Moreover, TIMM44 silencing/KO resulted in mitochondrial complex I inhibition, ATP depletion, mitochondrial membrane potential reduction, oxidative stress and DNA damage, and eventually provoked apoptosis. Conversely, ectopic overexpression of TIMM44 augmented glioma cell proliferation and migration. TIMM44 upregulation in glioma is possibly due to increased TIMM44 transcriptional machinery by the transcription factor GATA3 in a YME1L (YME1 Like 1 ATPase)-dependent manner. In vivo, the growth of subcutaneous glioma xenografts was suppressed after intratumoral injection of TIMM44 shRNA adeno-associated virus (AAV). TIMM44 depletion, ATP reduction, oxidative injury and apoptosis were detected in TIMM44 shRNA AAV-injected glioma xenografts. Moreover, the intracranial growth of TIMM44 KO glioma cells in the mouse brain was largely inhibited. Together, overexpressed TIMM44 could be a novel and promising therapeutic target of human glioma.

EXTH-27. MOLECULAR CHARACTERIZATION AND PRECLINICAL DEVELOPMENT OF NOVEL SMALL MOLECULE INHIBITOR SPECIFIC FOR WILD-TYPE IDH1 FOR FERROPTOSIS INDUCTION IN GLIOBLASTOMA

Abstract Increased de novo synthesis, mobilization and uptake of fatty acids are required to provide sufficient lipids for membrane biogenesis in support of rapid tumor cell division and growth. In addition to their structural roles as components of the plasma membrane, fatty acid-derived lipids regulate ferroptotic cell death, a type of programmed cell death, when oxidized by iron-dependent lipoxygenase enzymes. De novo lipogenesis and the defense against oxidative lipid damage require large amounts of cytosolic NADPH. Our group has recently found that HGG up-regulate wild-type Isocitrate dehydrogenase 1 (referred to hereafter as ‘wt-IDH1high HGG’) to generate large quantities of cytosolic NADPH. RNAi-mediated knockdown of wt-IDH1, alone and in combination with radiation therapy (RT), slows the growth of patient-derived HGG xenografts, while overexpression of wt-IDH1 promotes intracranial HGG growth. Isotope tracer and liquid chromatography-based lipidomic studies indicated that wt-IDH1 supports the de novo biosynthesis of mono-unsaturated fatty acids (MUFAs) and promotes the incorporation of monounsaturated phospholipids into the plasma membrane, while displacing polyunsaturated fatty acid (PUFA) phospholipids. In addition, enhanced NADPH production in wt-IDH1high HGG increases glutathione (GSH) level, reduces reactive oxygen species (ROS), activates the phospholipid peroxidase glutathione peroxidase 4 (GPX4)-driven lipid repair pathway, and dampens the accumulation of PUFA-containing lipid peroxides, known executioners of ferroptosis. To pharmacologically target wt-IDH1,we have used and characterized wt-IDH1i-13, a first-in-class competitive α,β-unsaturated enone (AbbVie). wt-IDH1i-13 potently inhibits wt-IDH1 enzymatic activity, by covalently binding to the NADP+ binding pocket. Our data indicate that wt-IDH1i-13 promotes ferroptosis, which can be rescued by pre-treatment of cells with the peroxyl scavenger and ferroptosis inhibitor ferrostatin. wt-IDH1i-13 is brain-penetrant, and similar to genetic ablation, reduces progression and extends the survival of wt-IDH1high HGG bearing mice, alone and in combination with RT. These studies credential to wt-IDH1i-13 as a novel therapeutic modality for the treatment of wt-IDH1 gliomas.