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Background Minimally Invasive Surgery Plus Recombinant Tissue Plasminogen Activator for Intracerebral Hemorrhage Evacuation (MISTIE) procedure was recently tested in a large phase III randomized trial showing a significant probability of functional benefit in those cases that reached the goal hematoma evacuation of ≤15 mL residual (or ≥70% removal). Benefit of thrombolysis was also identified in cases with large intraventricular hemorrhage, and achieving at least 85% volume reduction in the Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR) III trial. Objective To protocolize steps in the MISTIE and CLEAR procedures in order to maximize hematoma evacuation and minimize complications. Methods We articulate data-driven lessons and expert opinions surrounding the factors of patient selection, catheter placement, and dosing, which impacted safety and surgical performance in the MISTIE and CLEAR trials. Results Modifiable factors to maximize evacuation efficiency include optimizing catheter placement and pursuing aggressive dosing to achieve treatment goals, while strictly adhering to the safety steps as articulated in the respective trials. Prognostic factors that are viewed as nonmodifiable include greater initial intracerebral hemorrhage volume with irregular shape, smaller intraventricular bleeds, and the uncommon but consequential development of new bleeding during the dosing period despite strict protocol adherence. Conclusions Surgeon education in this tutorial is aimed at maximizing the benefit of the MISTIE and CLEAR procedures by reviewing case selection, safety steps, treatment objectives, and technical nuances. Key lessons include stability imaging, etiology screening, and technical adherence to the protocol in order to achieve defined thresholds of evacuation.

Background The American Stroke Association and the European Stroke Organization have established guidelines on cerebral venous thrombosis (CVT); however, questions remain when an individual case does not fall within the inclusion criteria on which these guidelines are based. This is relevant when considering the use of anticoagulation in cases of CVT regarding whether or not associated hemorrhage is present and whether the hemorrhage is currently expanding. Case Description A 16-year-old right-handed female G2P2 (gravidity 2 [2 pregnancies] and parity 2 [2 live births after at least 24 weeks) presented 8 days postpartum with complaints of slurred speech, right facial droop, and right upper extremity numbness that had progressed over the course of 4 hours before presentation. On imaging the patient had a CVT with associated hemorrhage progressing in size at serial 6-hour stability computed tomography scans for 24 hours post arrival. At 24 hours the patient went into disseminated intravascular coagulation and demonstrated signs of herniation. The patient underwent an emergency hemicraniectomy along with a right frontal external ventricular drain for intracranial pressure monitoring. Most recently, the patient had a Glasgow Coma Scale score of 15 and had a modified Rankin Scale score of 4 and was ultimately discovered to have antiphospholipid syndrome. Conclusions This case of CVT demonstrates the need for critically reading guidelines, as in this case the time to anticoagulation treatment was shorter than in cases included in guideline construction and repeated computed tomography examination demonstrated expansion suggesting it is unsuitable for immediate anticoagulation. Certain cases may fall outside of the study parameters on which guidelines are constructed, and clinicians should be aware of these exceptions.

Background Cavernous angiomas (CAs) are vascular malformations that may result in stroke. Case Description Herein, we evaluate a CA patient with chronic migraine who experienced 2 documented symptomatic hemorrhages after receiving respective high doses of botulinum toxin (Btx). Conclusions Recently, bacterial lipopolysaccharide has been reported to contribute to CA development through Toll-like receptor signaling, causing hemorrhagic angiogenic proliferation. Lipopolysaccharide and Btx share a common intracellular signaling pathway driving CA development and hemorrhage. Significance of these observations is demonstrated by previous works on plasma molecules showing prognostic associations with symptomatic hemorrhages in human CA, related to the same canonical pathways. Authors suggest careful tracking of the association of Btx and hemorrhage in CA patients.

Cavernous angiomas with symptomatic hemorrhage (CASH) have a high risk of rebleeding, and hence an accurate diagnosis is needed. With blood flow and vascular leak as established mechanisms, we analyzed perfusion and permeability derivations of dynamic contrast-enhanced quantitative perfusion (DCEQP) MRI in 745 lesions of 205 consecutive patients. Thirteen respective derivations of lesional perfusion and permeability were compared between lesions that bled within a year prior to imaging (N = 86), versus non-CASH (N = 659) using machine learning and univariate analyses. Based on logistic regression and minimizing the Bayesian information criterion (BIC), the best diagnostic biomarker of CASH within the prior year included brainstem lesion location, sporadic genotype, perfusion skewness, and high-perfusion cluster area (BIC = 414.9, sensitivity = 74%, specificity = 87%). Adding a diagnostic plasma protein biomarker enhanced sensitivity to 100% and specificity to 85%. A slightly modified derivation achieved similar accuracy (BIC = 321.6, sensitivity = 80%, specificity = 82%) in the cohort where CASH occurred 3–12 months prior to imaging after signs of hemorrhage would have disappeared on conventional MRI sequences. Adding the same plasma biomarker enhanced sensitivity to 100% and specificity to 87%. Lesional blood flow on DCEQP may distinguish CASH after hemorrhagic signs on conventional MRI have disappeared and are enhanced in combination with a plasma biomarker.

Background Differential diagnosis of sellar masses includes adenoma, meningioma, craniopharyngioma, and metastasis. Primary paraganglioma is seldom considered. We present a case of this unique pathology, review the relevant literature, and compile a compendium of immunohistochemical characteristics for use as a resource. Case Description A 73-year-old woman presented to the hospital with visual changes in her left hemifield. Noncontrast head computed tomography demonstrated a large sellar mass with suprasellar extension and displacement of the optic chiasm (diameter of 3.1 cm). Magnetic resonance imaging was unobtainable owing to an incompatible pacemaker. Computed tomography characterization was most consistent with a macroadenoma. Given the acute visual decline, surgical decompression via an endonasal transsphenoidal route was performed without complication. A diagnosis of paraganglioma was made based on histopathology. Following resection, the patient's visual field deficit improved. Computed tomography body imaging was negative for a metastatic origin. Conclusions Paraganglioma is a rare but potential differential diagnosis to consider when evaluating sellar masses.

Background and Purpose— Previously, murine models Krit1 +/− Msh2 −/ − and Ccm2 +/ − Trp53 −/ − showed a reduction or no effect on cerebral cavernous malformation (CCM) burden and favorable effects on lesional hemorrhage by the robust Rock (Rho-associated protein kinase) inhibitor fasudil and by simvastatin (a weak pleiotropic inhibitor of Rock). Herein, we concurrently investigated treatment of the more aggressive Pdcd10/Ccm3 model with fasudil, simvastatin, and higher dose atorvastatin to determined effectiveness of Rock inhibition. Methods— The murine models, Pdcd10 +/ − Trp53 −/ − and Pdcd10 +/ − Msh2 −/ − , were contemporaneously treated from weaning to 5 months of age with fasudil (100 mg/kg per day in drinking water, n=9), simvastatin (40 mg/kg per day in chow, n=11), atorvastatin (80 mg/kg per day in chow, n=10), or with placebo (n=16). We assessed CCM volume in mouse brains by microcomputed tomography. Lesion burden was calculated as lesion volume normalized to total brain volume. We analyzed chronic hemorrhage in CCM lesions by quantitative intensity of Perls staining in brain sections. Results— The Pdcd10 +/ − Trp53 −/ − /Msh2 −/ − models showed a mean CCM lesion burden per mouse reduction from 0.0091 in placebos to 0.0042 ( P =0.027) by fasudil, and to 0.0047 ( P =0.025) by atorvastatin treatment, but was not changed significantly by simvastatin. Hemorrhage intensity per brain was commensurately decreased by Rock inhibition. Conclusions— These results support the exploration of proof of concept effect of high-dose atorvastatin on human CCM disease for potential therapeutic testing.

Background More than a million Americans harbor a cerebral cavernous angioma (CA), and those who suffer a prior symptomatic hemorrhage have an exceptionally high rebleeding risk. Preclinical studies show that atorvastatin blunts CA lesion development and hemorrhage through inhibiting RhoA kinase (ROCK), suggesting it may confer a therapeutic benefit. Objective To evaluate whether atorvastatin produces a difference compared to placebo in lesional iron deposition as assessed by quantitative susceptibility mapping (QSM) on magnetic resonance imaging in CAs that have demonstrated a symptomatic hemorrhage in the prior year. Secondary aims shall assess effects on vascular permeability, ROCK activity in peripheral leukocytes, signal effects on clinical outcomes, adverse events, and prespecified subgroups. Methods The phase I/IIa placebo-controlled, double-blinded, single-site clinical trial aims to enroll 80 subjects randomized 1-1 to atorvastatin (starting dose 80 mg PO daily) or placebo. Dosing shall continue for 24-mo or until reaching a safety endpoint. Expected outcomes The trial is powered to detect an absolute difference of 20% in the mean percent change in lesional QSM per year (2-tailed, power 0.9, alpha 0.05). A decrease in QSM change would be a signal of potential benefit, and an increase would signal a safety concern with the drug. Discussion With firm mechanistic rationale, rigorous preclinical discoveries, and biomarker validations, the trial shall explore a proof of concept effect of a widely used repurposed drug in stabilizing CAs after a symptomatic hemorrhage. This will be the first clinical trial of a drug aimed at altering rebleeding in CA.

Introduction: Therapeutic interest into the neurotrophins resides in their ability to regulate the process of neuronal and synaptic regeneration following acute brain injuries such as intracerebral hemorrhage, subarachnoid hemorrhage and ischemic stroke. P75 neurotrophic receptor (p75NTR) is an important receptor for the role of neurotrophins in modulating brain plasticity and apoptosis. The current understanding of the role of p75NTR in cellular adaptation following pathological insults remains blurred. Methods: We identified p75NTR and related genes through extensive data mining of a PubMed literature search including published works related to p75NTR from the past 20 years. Bioinformatic network and pathway analyses of identified genes (n=235) were performed using ReactomeFIViz in Cytoscape based on the highly reliable Reactome functional interaction network algorithm. This approach merges interactions extracted from human curated pathways with predicted interactions from machine learning. Results: Genome-wide pathway analysis showed total of 16 enriched hierarchical clusters. A total of 278 enriched single pathways were also identified (pp75NTR gene network. This study provides a comprehensive analysis and investigation into the current knowledge of p75NTR signaling networks and pathways. Discussion: This study provides the largest comprehensive gene and functional network library of p75NTR and incorporates current knowledge using a large dataset approach that increases the overall understanding of complex p75NTR networks. These results suggest both new possible target genes for further investigation in p75NTR research, while also validating previously conducted research. These results can be used to generate novel hypotheses to gain a greater understanding of p75NTR in stroke. Future directions: We are currently sequencing miRNA libraries from ischemic and hemorrhagic stroke patients’ plasma with longitudinal plasma samples and clinical data. This data together with presented results will be used to test identified novel targets in p75NTR engineered models in order seek novel therapeutic strategies to increase recovery after stroke.

P75 neurotrophic receptor (p75NTR) is an important receptor for the role of neurotrophins in modulating brain plasticity and apoptosis. The current understanding of the role of p75NTR in cellular adaptation following pathological insults remains blurred, which makes p75NTR’s related signaling networks an interesting and challenging initial point of investigation. We identified p75NTR and related genes through extensive data mining of a PubMed literature search including published works related to p75NTR from the past 20 years. Bioinformatic network and pathway analyses of identified genes (n = 235) were performed using ReactomeFIViz in Cytoscape based on the highly reliable Reactome functional interaction network algorithm. This approach merges interactions extracted from human curated pathways with predicted interactions from machine learning. Genome-wide pathway analysis showed total of 16 enriched hierarchical clusters. A total of 278 enriched single pathways were also identified (p p75NTR gene network. This study provides a comprehensive analysis and investigation into the current knowledge of p75NTR signaling networks and pathways. These results also identify several genes and their respective protein products as involved in the p75NTR network, which have not previously been clearly studied in this pathway. These results can be used to generate novel hypotheses to gain a greater understanding of p75NTR in acute brain injuries, neurodegenerative diseases and general response to cellular damage.

Background The extent of intracerebral hemorrhage (ICH) removal conferred survival and functional benefits in the minimally invasive surgery with thrombolysis in intracerebral hemorrhage evacuation (MISTIE) III trial. It is unclear whether this similarly impacts outcome with craniotomy (open surgery) or whether timing from ictus to intervention influences outcome with either procedure. Objective To compare volume evacuation and timing of surgery in relation to outcomes in the MISTIE III and STICH (Surgical Trial in Intracerebral Hemorrhage) trials. Methods Postoperative scans were performed in STICH II, but not in STICH I; therefore, surgical MISTIE III cases with lobar hemorrhages (n = 84) were compared to STICH II all lobar cases (n = 259) for volumetric analyses. All MISTIE III surgical patients (n = 240) were compared to both STICH I and II (n = 722) surgical patients for timing analyses. These were investigated using cubic spline modeling and multivariate risk adjustment. Results End-of-treatment ICH volume ≤28.8 mL in MISTIE III and ≤30.0 mL in STICH II had increased probability of modified Rankin Scale (mRS) 0 to 3 at 180 d (P = .01 and P = .003, respectively). The effect in the MISTIE cohort remained significant after multivariate risk adjustments. Earlier surgery within 62 h of ictus had a lower probability of achieving an mRS 0 to 3 at 180 d with STICH I and II (P = .0004), but not with MISTIE III. This remained significant with multivariate risk adjustments. There was no impact of timing until intervention on mortality up to 47 h with either procedure. Conclusion Thresholds of ICH removal influenced outcome with both procedures to a similar extent. There was a similar likelihood of achieving a good outcome with both procedures within a broad therapeutic time window.

Cavernous angiomas (CA) are common vascular anomalies causing brain hemorrhage. Based on mouse studies, roles of gram-negative bacteria and altered intestinal homeostasis have been implicated in CA pathogenesis, and pilot study had suggested potential microbiome differences between non-CA and CA individuals based on 16S rRNA gene sequencing. We here assess microbiome differences in a larger cohort of human subjects with and without CA, and among subjects with different clinical features, and conduct more definitive microbial analyses using metagenomic shotgun sequencing. Relative abundance of distinct bacterial species in CA patients is shown, consistent with postulated permissive microbiome driving CA lesion genesis via lipopolysaccharide signaling, in humans as in mice. Other microbiome differences are related to CA clinical behavior. Weighted combinations of microbiome signatures and plasma inflammatory biomarkers enhance associations with disease severity and hemorrhage. This is the first demonstration of a sensitive and specific diagnostic microbiome in a human neurovascular disease., Gut microbiome has been linked to cavernous angioma (CA), a common vascular disease, but the role in humans remains unclear. Here, the authors combine 16S rRNA sequencing and shotgun metagenomics to profile the microbiome in a large cohort of human subjects with and without CA, and among subjects with different CA clinical features.

Brain senescence is associated with impaired endothelial barrier function, angiogenic and inflammatory activity, and propensity to brain hemorrhage. The same pathological changes occur in cerebral cavernous malformations (CCM), a genetic neurovascular anomaly. We hypothesized common transcriptomic and plasma cytokine signatures in the aging brain and CCM. We identified 320 genes [fold change ≥1.5; p

Introduction: Studies on the natural clinical course of Cavernous Angioma (CA) have reported a Methods: Patients with CA diagnosis were prospectively enrolled in IRB approved database from 09/2009 to 02/2019 (N=327). Imaging and clinical follow-up were recommended annually, or sooner with new symptoms. Patients with 1 or more CA with maximum diameter >4 mm on T2 MRI, not excised or irradiated, and 1 or more clinical/imaging follow-up were included (N=192). New AH and SH were assessed per prospectively articulated criteria, and rates were estimated per lesion-year and patient-year, and NLF in familial cases. Results: There were no demographic or disease confounders among cases included and excluded from the study cohort, except for higher rates of prior SH and greater prevalence of cases with solitary lesion excluded because of surgical treatment. Total follow-up was 410 patient-years (2539 lesion-years). During prospective follow-up, the rate of AH was higher than the rate of SH (12.9% vs. 7.5% per patient-year and 2.1% vs. 1.2% per lesion -year, p=0.02 and p=0.01 respectively). Patients presenting with SH in the prior year had higher rate of AH than those presenting incidentally or with seizures (19.83% and 8.2% per patient-year respectively; p=0.003). A higher rate of NLF on T2 (p=0.0002) and SWI (p=0.0004) was also observed in patients with prior SH compared to stable patients. After an AH, 3 of 6 sporadic patients with solitary lesion and only 2 of 28 familial cases with multiple lesions underwent surgical resection of the lesion with AH. Conclusions: Subclinical imaging changes are more common than SH during prospective follow-up of CAs. They are more common in patients presenting with prior SH, and likely reflect a more sensitive biomarker of CA instability. AH more likely provokes a surgical decision in cases with solitary lesion than in familial cases with multiple lesions.

Introduction: Previous studies have reported robust inflammatory cell infiltration, selective synthesis of IgG, B-cell clonal expansion, and deposition of immune complexes and complement within Cerebral Cavernous Malformation (CCM) lesions. Furthermore,B-cell depletion has been shown to reduce the maturation of CCM in murine models. We hypothesize that specific autoantigen(s) within the lesional milieu trigger the pathogenetic immune responses in CCMs. This study aims to identify those putative autoantigen(s) using recombinant antibodies (rAbs) derived from plasma cells found in surgical human CCM lesions. Methods: CD138 + plasma cells were laser captured from fresh frozen surgically resected human CCM lesions. Clonally expanded immunoglobulin heavy- and light-chain variable region pairs were cloned into IgG expression vectors and expressed as monoclonal antibodies. Purified rAbs were assayed by immunofluorescence with CCM lesion tissue and normal brain tissue sections. rAbs assayed by immunocytochemistry with human primary cell line were used to further define the staining pattern. The cell lysates were immunoprecipitated with rAb, after protein purification by SDS-PAGE, and analyzed by Mass spectrometry. Results: In normal brain tissue, rAbs stained endothelial cells with limited staining of glial cells. In CCM lesional tissue, rAbs stained endothelial cells, glial cells as well as structures in the acellular matrix adjacent to caverns. In cultured Human Brain Microvascular Endothelial Cells (HBMECs) and Human Astrocytes (HAs), rAbs co-localized with cytoplasmic components. After HBMEC and HA cell lysates were immunoprecipitated with rAb, a Coomassie Stain detected bands of approximately 50 kDa. Conclusions: Our results suggest that autoantigen(s) in human CCM lesions are cytoplasmic components present in lesional tissue as well as in normal brain tissue. Molecular level identification of the triggering antigen is still ongoing by mass spectrometry. Identification of the autoantigen(s) in the lesional milieu might explain the propensity of lesion development from leaky endothelium in the neuroglial parenchyma. Characterization of the autoantigen triggers will open new venues for therapy or vaccine in this disease.

Introduction: The Minimally Invasive Surgery Plus Recombinant Tissue Plasminogen Activator for Intracerebral Hemorrhage Evacuation Phase III trial (MISTIE III) concluded that the extent of hematoma reduction confers a mortality and functional benefit. It is unclear if a minimum extent of evacuation is needed for mortality and functional outcome benefit in lobar cases with MISTIE and with open surgical interventions. Objective: We analyzed the effect of extent of lobar ICH evacuation on clinical outcome at 180 days after undergoing the MISTIE procedure and open craniotomy, in the context of the MISTIE III and STICH II clinical trials, respectively. Methods: Patients randomized to the surgical arm with lobar ICH, who underwent the procedure in the MISTIE III trial (n=84) and the STICH II trial (n=266) were analyzed, excluding cases crossing over to surgery. We assessed end of treatment ICH volume on post procedure CT scans and % hematoma evacuation, in relation to survival and likelihood of mRS 0-3. Cubic spline modeling with dichotomized outcome was used to compare the extent of hematoma evacuation on clinical outcome. Results: End of treatment volume of < 28 mL in lobar ICH MISTIE III patients and < 30 mL in STICH II trial patients showed a significantly increased probability of achieving an mRS of 0-3 at 180 days (p Conclusion: This analysis confirms that extent of hematoma evacuation is important in attaining the benefits of both minimally invasive and open surgical interventions in non-herniating lobar ICH patients randomized in clinical trials. Extent of ICH evacuation must be considered in the analysis of comparative effectiveness of various techniques and in the design of future trials.

Introduction: Completion of the MISTIE procedure requires a period of hematoma stability before and during hematoma removal and, if necessary, dosing of rtPA which can take days to complete. Early surgery was intended in the STICH I and II trials, yet was performed after varying delays. No previous analysis has evaluated the timing for hematoma removal on outcomes in these trials. Objective: Determine if time from ictus to completion of hematoma removal may have affected patient outcome in three large surgical clinical trials of ICH evacuation. Methods: Patients randomized to surgery in the MISTIE III (n=242), STICH I (n=464) and STICH II (n=266) trials who received the procedure were analyzed, excluding cases crossing over to surgery. Time from ictus to end of treatment, defined as 24 hours after last dose in (MISTIE III) or time to craniotomy (STICH I and II), was analyzed in relation to likelihood of survival and functional outcome at 180 days. Cubic spline models with dichotomized outcomes were used. Results: The probability of achieving an mRS 0-3 increased significantly with longer time until completion of the procedure, up to 83 hours post-ictus, and worsened with longer delays thereafter (p=0.05). Better mRS was also achieved in STICH I patients with longer time until surgical removal, up to 60 hours post-ictus (p=0.0002), but not with longer delays (p=0.49). In STICH II (lobar cases), there was greater likelihood of mRS 0-3 with longer delay after 22 hours post-ictus (p=0.004), but not with earlier surgery (p=0.19). There was no significant benefit in survival, with earlier intervention across modalities and trials. Adjustment by initial hematoma volume further validated that early procedures do not favor survival or achieving a mRS 0-3. Conclusion: Early hematoma evacuation up to 60-80 hours post-ictus does not increase the probability of survival nor a good functional outcome in non-herniating ICH patients included in clinical trials, likely in view of bleeding instability. This was true in minimally invasive intervention as well as open surgeries.

Background: Cellular senescence is associated with gene expression dysregulation affecting endothelial barrier function as well as angiogenic and inflammatory processes. These pathological changes occur in cerebral cavernous malformations (CCMs), a neurovascular anomaly predisposing patients to hemorrhagic stroke. We hypothesize common transcriptomic and biomarker signatures between the aging brain and CCMs. Method: Brain specific genes dysregulate in Younger (age < 30) and Older (age > 50) human brain parenchyma were identified using the Genotype-Tissue Expression database, and compared with differential transcriptome in microdissected neurovascular units of human CCM lesions. Brain white matter vascular permeability in areas devoid of lesions was measured in non-CCM (23 Younger, 27 Older), Sporadic-CCM (S-CCM) (26 Younger, 37 Older) and Familial-CCM (F-CCM) (41 Younger, 17 Older) using dynamic contrast-enhanced quantitative perfusion MRI. Plasma levels of 6 proteins with reported roles in CCMs were quantified, including VEGF, angiopoietin (ANG 1 & 2), CRP, thrombospondin 2 (THBS 2), and endoglin (ENG). All reported correlations were significant at P< 0.05, FDR corrected. Result: We identified 320 genes (absolute fold change≥1.5) commonly dysregulated in aging brain and CCM, related to inflammation and extracellular matrix organization pathways. Brain permeability was greater in Older non-CCM and S-CCM compared to Younger subjects. Brain permeability was higher in Younger F-CCM harboring germ line CCM mutations, than in both Younger non-CCM (p Conclusion: There are common transcriptomic, and brain permeability and plasma biomarker signatures in the aging brain and CCM, suggesting common dysregulated pathways. Biomarkers and potential therapies identified in a well characterized Mendelian neurovascular disease may be applicable to mitigate the same mechanistic aberrations in the aging brain.

Preclinical studies indicate that up-regulation of carbonic anhydrase (CA) by temozolomide (TMZ), via a mechanism requiring the proto-oncogene BCL-3, promotes resistance to therapy in glioblastoma (GBM) cells. Moreover, the CA inhibitor, acetazolamide (ACZ), sensitizes patient-derived GBM cells and xenografts to TMZ. These findings led to the current Phase I study investigating the safety and efficacy of adding ACZ to adjuvant TMZ in patients with newly diagnosed, MGMT-methylated malignant glioma. 24 patients were enrolled (23 GBM and one Grade III IDH-mutant astrocytoma), median age was 53.5 and mean KPS 91. ACZ was given on days 1-21 of each adjuvant TMZ cycle (250 mg BID days 1-7, increased to 500 mg BID days 8-21). No patient experienced the primary outcome of regimen limiting toxicity (RLT) and there were only three grade III adverse events deemed likely unrelated to ACZ. For the secondary endpoints of overall and progression free survival (OS and PFS, respectively), only the 23 GBM patients were included (22 IDH-wildtype and 1 IDH-mutant). From diagnosis, median PFS was 18.8 months (95% CI: 10.4-23.0) and median OS was 25.0 months (95% CI: 19.9-28.4). Median time from diagnosis to consent was 2.9 months. As of April 2021, only 7 of 23 deaths had occurred. 2-year OS% was 68.2%. Further analysis of secondary endpoints including 6-month objective response rate (ORR) and biomarker analysis of BCL-3 by IHC will be available in the coming months. In sum, the data indicate that addition of ACZ to TMZ is safe and does not lead to reduced TMZ dosing. Also, compared to historical data, interim outcomes suggest that addition of ACZ may substantially improve PFS and 2-year overall survival. These findings support the hypothesis that ACZ acts as a chemosensitizer of alkylating chemotherapy in GBM and support examination of this regimen in a randomized, placebo-controlled study.

Cerebral cavernous malformations (CCMs) are dilated capillaries causing epilepsy and stroke. Inheritance of a heterozygous mutation in CCM3/PDCD10 is responsible for the most aggressive familial form of the disease. Here we studied the differences and commonalities between the transcriptomes of microdissected lesional neurovascular units (NVUs) from acute and chronic in vivo Ccm3/Pdcd10ECKO mice, and cultured brain microvascular endothelial cells (BMECs) Ccm3/Pdcd10ECKO. We identified 2409 differentially expressed genes (DEGs) in acute and 2962 in chronic in vivo NVUs compared to microdissected brain capillaries, as well as 121 in in vitro BMECs with and without Ccm3/Pdcd10 loss (fold change ≥ |2.0|; p

BACKGROUND The natural history and management of dural ectasia in Neurofibromatosis 1 (NF1) is still largely unknown. Dural ectasias are one of the common clinical manifestations of NF1; however, the treatment options for dural ectasias remain unstudied. OBJECTIVE To investigate the natural history, diagnosis, management, and outcome of the largest case series of patients with NF1-associated dural ectasia to date. METHODS Records from our NF1 clinic were reviewed to identify NF1 patients with computed tomography or magnetic resonance imaging evidence of dural ectasia(s) to determine their clinical course. Demographics, symptoms, radiographic and histopathologic findings, treatment, and clinical course were assessed. RESULTS Thirty-four of 37 patients were managed without surgery. Of the 18 initially asymptomatic patients, 5 (27.8%) progressed to symptoms attributable to a dural ectasia (onset of 2.7% per patient-year). Three patients required surgical intervention because of extraspinal mass effect. All 3 initially improved but had symptom recurrence within 2 yr. Reoperation involved shunt placement for cerebrospinal fluid (CSF) diversion. On imaging review, 26 (76.5%) of the nonsurgical patients harbored an associated nearby plexiform neurofibroma. Pathology of one surgical case revealed dural infiltration by diffuse neurofibroma. CONCLUSION Using the largest NF1-associated dural ectasia group to date, we report the first symptom-onset rate for nonsurgical patients. In the few cases requiring surgery for decompression, primary resection, and patching of ectasias failed, subsequently requiring CSF shunting. We demonstrate imaging evidence of nearby plexiform neurofibroma in a majority of cases, which, when combined with histopathology, provides a novel explanation for the formation of dural ectasias.

The purpose of this study was to determine important genes, functions, and networks contributing to the pathobiology of cerebral cavernous malformation (CCM) from transcriptomic analyses across 3 species and 2 disease genotypes. Sequencing of RNA from laser microdissected neurovascular units of 5 human surgically resected CCM lesions, mouse brain microvascular endothelial cells, Caenorhabditis elegans with induced Ccm gene loss, and their respective controls provided differentially expressed genes (DEGs). DEGs from mouse and C. elegans were annotated into human homologous genes. Cross-comparisons of DEGs between species and genotypes, as well as network and gene ontology (GO) enrichment analyses, were performed. Among hundreds of DEGs identified in each model, common genes and 1 GO term (GO:0051656, establishment of organelle localization) were commonly identified across the different species and genotypes. In addition, 24 GO functions were present in 4 of 5 models and were related to cell-to-cell adhesion, neutrophil-mediated immunity, ion transmembrane transporter activity, and responses to oxidative stress. We have provided a comprehensive transcriptome library of CCM disease across species and for the first time to our knowledge in Ccm1/Krit1 versus Ccm3/Pdcd10 genotypes. We have provided examples of how results can be used in hypothesis generation or mechanistic confirmatory studies.

Background: Cerebral cavernous malformation (CCM) patients have lesions comprised of dilated capillaries in the brain. Despite the knowledge that mutations of three CCM genes can cause this disease, other genetic and environmental factors that contribute to lesion formation are likely given the highly variable disease expression. Genome-wide association studies in CCM cohorts and mouse models of CCM, both point to a role of lipopolysaccharide. Mouse studies have shown that the microbiome, particularly Gram-negative bacteria, drive CCM lesion development. These data point to a possibility that CCM disease is affected by the gut microbiome. In this study, we investigated if human CCM disease could be linked to the gut microbiome. Methods: Fecal samples from 88 CCM patients, from four sites, were assayed using 16S rRNA gene sequencing. Following taxonomic classification by exact sequence variant analysis (ESV) using DeBlur, microbiome composition was compared with those of a reference non-CCM population (n=348), or between subgroups of CCM patients based on clinical data elements. Results: Analyses of microbiome composition statistics identified bacterial ESVs belonging to Clostridiales , Lachnospiraceae, Ruminococcaceae , and the genus Bacteroides that were significantly enriched in CCM patients compared to healthy controls. Within our CCM cohort, patients with germline CCM mutations had stool-associated enrichment of ESVs annotated to Clostridiales, and the genera Bacteroides and Prevotella , when compared to sporadic CCM patients, while patients with CCM1 and CCM2 mutations had different proportions of Clostridiales, Lachnospiraceae, and the genus Ruminococcus . Furthermore, Lachnospiraceae and Bacteroides proportions differentiated disease aggressiveness (All p Conclusions: These data are the first to show that CCM patients have a distinct microbiome signature. Germline mutation and disease aggressiveness can correlate with further unique microbiome composition. This study supports further investigation into the mechanistic link between CCM disease and the microbiome. This will enhance our understanding of the brain-gut axis in CCM disease and the use of microbiome as a therapeutic target.

Introduction: Cerebral cavernous angiomas with a documented symptomatic hemorrhage (CASH) are associated with an exceptionally high risk of recurrent hemorrhage and serious morbidity. It is unclear if peripheral blood plasma biomarkers implicated in disease biology can differentiate CASH, and whether the same or different biomarkers can distinguish cases who would rebleed. Methods: Eighteen plasma molecules with postulated mechanistic roles in this disease were quantified in 114 patients and 12 healthy subjects. The best biomarker combination differentiating CASH in the prior year (+/- 30 days) was derived by minimizing the Akaike Information Criterion (AIC), and was validated using statistical and machine-learning simulations. This was compared to the biomarker predicting bleeding in the subsequent year (+/- 30 days), and both explanatory and predictive biomarkers were followed longitudinally in a subset of cases. Results: Nine plasma molecules had significantly different levels expressed in CASH patients (p Conclusions: Our results suggest shared and unique biomarkers of recent symptomatic hemorrhage and of future bleeding in cavernous angiomas. This may be applied for risk stratification in clinical trials, and potentially developed as a tool in clinical practice.