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The prehospital phase is a critical component of delivering high-quality acute stroke care. This topical review discusses the current state of prehospital acute stroke screening and transport, as well as new and emerging advances in prehospital diagnosis and treatment of acute stroke. Topics include prehospital stroke screening, stroke severity screening, emerging technologies to aid in the identification and diagnosis of acute stroke in the prehospital setting, prenotification of receiving emergency departments, decision support for destination determination, and the capabilities and opportunities for prehospital stroke treatment in mobile stroke units. Further evidence-based guideline development and implementation of new technologies are critical for ongoing improvements in prehospital stroke care.

Chronic subdural hematoma (CSDH) is an increasingly prevalent disease in the aging population. Patients with CSDH frequently suffer from concurrent vascular disease or develop secondary thrombotic complications requiring antithrombotic treatment.To determine the safety and impact of early reinitiation of antithrombotics after middle meningeal artery embolization for chronic subdural hematoma.This is a single-institution, retrospective study of patients who underwent middle meningeal artery (MMA) embolizations for CSDH. Patient with or without antithrombotic initiation within 5 days postembolization were compared. Primary outcome was the rate of recurrence within 60 days. Secondary outcomes included rate of reoperation, reduction in CSDH thickness, and midline shift.Fifty-seven patients met inclusion criteria. The median age was 66 years (IQR 58-76) with 21.1% females. Sixty-six embolizations were performed. The median length to follow-up was 20 days (IQR 14-44). Nineteen patients (33.3%) had rapid reinitiation of antithrombotics (5 antiplatelet, 11 anticoagulation, and 3 both). Baseline characteristics between the no antithrombotic (no-AT) and the AT groups were similar. The recurrence rate was higher in the AT group (no-AT vs AT, 9.3 vs 30.4%, P = .03). Mean absolute reduction in CSDH thickness and midline shift was similar between groups. Rate of reoperation did not differ (4.7 vs 8.7%, P = .61).Rapid reinitiation of AT after MMA embolization for CSDH leads to higher rates of recurrence with similar rates of reoperation. Care must be taken when initiating antithrombotics after treatment of CSDH with MMA embolization.

Medically refractory idiopathic intracranial hypertension (IIH) is frequently treated with venous sinus stenosis stenting with high success rates. Patient selection has been driven almost exclusively by identification of supraphysiological venous pressure gradients across stenotic regions based on theoretical assessment of likelihood of response.To explore the possibility of benefit in low venous pressure gradient patients.Using a single-center, prospectively maintained registry of patients with IIH undergoing venous stenting, we defined treatment groups by gradient pressures of ≤4, 5 to 8, and8 mmHg based on the most frequently previously published thresholds for stenting. Baseline demographics, clinical, and neuro-ophthalmological outcomes (including optical coherence tomography and Humphrey visual fields) were compared.Among 53 patients, the mean age was 32 years and 70% female with a mean body mass index was 36 kg/m 2 . Baseline characteristics were similar between groups. The mean change in lumbar puncture opening pressure at 6 months poststenting was similar between the 3 groups (≤4, 5-8, and8 mmHg; 13.4, 12.9, and 12.4 cmH 2 O, P = .47). Papilledema improvement was observed across groups at 6 months (100, 93, and 86, P = .7) as were all clinical symptoms. The mean changes in optical coherence tomography retinal nerve fiber layer (-30, -54, and -104, P = .5) and mean deviation in Humphrey visual fields (60, 64, and 67, P = .5) at 6 weeks were not significantly different.Patients with IH with low venous pressure gradient venous sinus stenosis seem to benefit equally from venous stenting compared with their higher gradient counterparts. Re-evaluation of our restrictive criteria for this potentially vision sparing intervention is warranted. Future prospective confirmatory studies are needed.

Introduction: Automated LVO detection from CT angiography may improve treatment times in LVO acute ischemic stroke (AIS), as suggested by prior single center non-randomized studies. Here, we perform a cluster randomized trial to evaluate this question with improved rigor. Methods: We performed a cluster randomized stepped wedge clinical trial across four comprehensive stroke centers January 2021 to February 2022. An automated LVO detection software (Viz.AI) was implemented at the 4 hospitals in a stepped fashion, with a randomly determined order (Figure 1). We included patients who underwent EVT. Patients presenting within the 2-week software transition period were excluded. The primary outcome was door-to-groin puncture time (DTG) adjusted for age, sex and NIHSS and was determined using a mixed-effect linear regression, with a random effect for cluster (hospital site) and fixed effect for exposure status. Results: Among 249 patients that met inclusion criteria, median age was 67 [IQR 57-79], NIHSS 17 [IQR 11-22] and 50.6% were female. Median time from last known well to arrival was 222 minutes and 90% had ASPECTS ≥ 8. A total of 199 patients were treated in the unexposed period and 50 in the exposed. In univariable analysis, median DTG improved in the unexposed vs. exposed periods (91 min [IQR 63 - 108 min] vs. 73 [IQR 32-102 min], p Discussion: In a multi-center cluster randomized trial, implementation of an automated LVO detection algorithm improved treatment times in patients with LVO AIS.

Introduction: Automated LVO detection and software-based care team integration has been shown to improve door-to-groin time metrics at comprehensive stroke centers (CSCs). The impact of this software on accelerating transfers out of primary stroke centers (PSCs) for LVO AIS patients remains undetermined. Methods: We performed a prospective cohort study across 11 stroke centers (7 PSCs and 4 CSCs) in the greater Houston area from January 1st 2021 - February 24th 2022. An automated LVO detection and workflow manager software (Viz.AI) was implemented at all the hospitals. Patients were included if they were diagnosed with LVO AIS based on CT angiogram at a PSC and were transferred to CSC. Patients who presented during a 2-week transition period at the time of LVO detection software activation were excluded. The primary outcome was time from PSC arrival to departure to CSC (door-in-door-out, DIDO) before and after software implementation and was performed using the Wilcoxon rank sum test (STATA v.15). Results: Among 234 patients that met inclusion criteria, median age was 65 [58-76] years, NIHSS 3 [1-8] and 45% were female. Mean time from last known well to PSC arrival was 512 +/- 281 minutes and mean DIDO was 176 +/- 77 min. A total of 156 patients were evaluated in the pre-software implementation period and 78 after. There were no significant differences in the pre- and post-implementation cohorts with respect to age, risk factors (HTN, HLD, Afib, carotid disease, diabetes), although a greater proportion of patients in the pre-implementation phase were female (52% vs. 31%, p Discussion: In this multicenter cohort study, implementation of automated LVO detection with coupled care-team communication tool improved PSC transfer performance by over 30 minutes. These findings corroborate the findings for care acceleration at CSCs with similar software implementations.

Introduction: Recent randomized controlled trials (RCT) failed to demonstrate non-inferiority of skipping IV tPA in patients with planned endovascular therapy (EVT). None of these studies included patients from the US due to regulatory challenges. Given practice patterns vary relative to Asia and Europe, we sought to address this topic using a validated alternative to RCTs, fuzzy regression discontinuity design (RDD). Methods: From our prospectively maintained multi-center registry we identified patients with LVO AIS treated with EVT with and without IV tPA treatment from 1/2018 - 9/2021. We used the time cutoff for IV tPA as our discontinuity and assumed subjects on either side of the cutoff have markedly different probabilities of receiving the treatment but are similar in other relevant characteristics. The primary outcome was good functional outcome defined as 90-day mRS 0-2 and it was compared between these two populations immediately adjacent to the cutoff using local linear regressions. Results: Among 694 patients with LVO AIS who received EVT, median age was 69 [IQR 59-79], 50%, were female, 44% White, 24% Black, and 14% Hispanic. 51% received IV tPA, with median onset to treatment time of 109 min [IQR 79-160]. We observed a sharp drop (47%) in the probability of tPA around the cutoff time of 4 hours (allowing 30 minutes for in-hospital evaluation), while there were no significant differences in other relevant features at the cutoff, validating the underlying RDD assumptions (Figure A). Overall, 33% of patients achieved good functional outcomes and there were no significant differences around the cutoff time (Figure B). In fuzzy RDD, there was no evidence of an association of receiving tPA with good functional outcome with regression discontinuity of only 1.0% (p=0.98) Conclusion: Our study provides the highest quality US-based evidence supporting the findings of the outside US trials, demonstrating no benefit of skipping IV tPA in patients with planned EVT.

BackgroundRandomized trials have not demonstrated benefit from intravenous thrombolysis among patients undergoing endovascular thrombectomy (EVT). However, these trials included primarily patients presenting directly to an EVT capable hub center. We sought to study outcomes for EVT candidates who presented to spoke hospitals and were subsequently transferred for EVT consideration, comparing those administered alteplase at spokes (i.e., ‘drip-and-ship’ model) versus those not.MethodsConsecutive EVT candidates presenting to 25 spokes from 2018 to 2020 with pre-transfer CT angiography defined emergent large vessel occlusion and Alberta Stroke Program CT score ≥6 were identified from a prospectively maintained Telestroke database. Outcomes of interest included adequate reperfusion (Thrombolysis in Cerebral Infarction (TICI) 2b–3), intracerebral hemorrhage (ICH), discharge functional independence (modified Rankin Scale (mRS) ≤2), and 90 day functional independence.ResultsAmong 258 patients, median age was 70 years (IQR 60–81), median National Institutes of Health Stroke Scale (NIHSS) score was 13 (6-19), and 50% were women. Ninety-eight (38%) were treated with alteplase at spokes and 113 (44%) underwent EVT at the hub. Spoke alteplase use independently increased the odds of discharge mRS ≤2 (adjusted OR 2.43, 95% CI 1.08 to 5.46, p=0.03) and 90 day mRS ≤2 (adjusted OR 3.45, 95% CI 1.65 to 7.22, p=0.001), even when controlling for last known well, NIHSS, and EVT; it was not associated with an increased risk of ICH (OR 1.04, 95% CI 0.39 to 2.78, p=0.94), and there was a trend toward association with greater TICI 2b–3 (OR 3.59, 95% CI 0.94 to 13.70, p=0.06).ConclusionsIntravenous alteplase at spoke hospitals may improve discharge and 90 day mRS and should not be withheld from EVT eligible patients who first present at alteplase capable spoke hospitals that do not perform EVT. Additional studies are warranted to confirm and further explore these benefits.

Carotid artery stenosis is a leading cause of ischemic stroke. While management of symptomatic carotid stenosis is well established, the optimal approach in asymptomatic carotid artery stenosis (aCAS) remains controversial. The rapid evolution of medical therapies within the time frame of existing landmark aCAS surgical revascularization trials has rendered their findings outdated. In this review, we sought to summarize the controversies in the management of aCAS by providing the most up-to-date medical and surgical evidence. Subsequently, we compile the evidence surrounding high-risk clinical and imaging features that might identify higher-risk lesions. With this, we aim to provide a practical framework for a precision medicine approach to the management of aCAS.

Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.

Background Venous sinus stenosis (VSS) stenting has emerged as an effective treatment for patients with Idiopathic Intracranial Hypertension (IIH). However, stenting carries risk of in-stent stenosis/thrombosis and cumulative bleeding risk from long-term dual antiplatelet (DAPT) use. Thus, we investigated the potential safety and efficacy of primary balloon angioplasty as an alternative to stenting in IIH. Methods A prospectively maintained single-center registry of IIH patients undergoing endovascular procedures was queried. Inclusion criteria included patients with confirmed IIH and angiographically demonstrable VSS who underwent interventions from 2012- 2021. Patients were dichotomized into primary balloon angioplasty (Group A) and primary stenting (Group S), comparing clinical outcomes using bivariate analyses. Results 62 patients were included with median age of 33 [IQR 26-37], 74% females. Group A (9/62) and Group S (53/62) had similar baseline characteristics. Papilledema improvement was higher in Group S at 6 weeks and 6 months (44 vs. 93, p = 0.002 and 44 vs. 92%, p = 0.004), with similar improvements across all symptoms. Group S had higher mean post-procedure venous pressure gradient change (8 vs. 3 mmHg, p = 0.02) and a lower CSF opening pressure at 6 months (23 vs. 36 cmH2O, p Conclusions Primary VSS balloon angioplasty provides a marginal and short-lived improvement of IIH symptoms compared to stenting. These findings suggest a cautious and limited role for short-term rescue angioplasty in poor shunting and stenting candidates with refractory IIH.

This meeting abstract was removed due to the OA licensing requirements of this journal. The full abstract is listed here : https://www.svin.org/files/SVIN_2021_Abstracts_for_Web.pdf

This meeting abstract was removed due to the OA licensing requirements of this journal. The full abstract is listed here : https://www.svin.org/files/SVIN_2021_Abstracts_for_Web.pdf

Introduction : The number of thrombectomy passes during endovascular therapy (EVT) for large vessel occlusion (LVO) in acute ischemic stroke (AIS) has been associated with probability of favorable functional outcome, with worse outcomes correlating with greater pass number. While first‐pass recanalization is a strong predictor of functional outcomes, the optimal or maximum recommended number of passes at which patients continue to benefit from EVT remains controversial. Moreover, among patients requiring more attempts, it is unclear if a certain subset of patients continue to benefit despite multiple passes. In this study, we determine predictors of functional outcome among patients requiring a high pass number to achieve successful vessel recanalization. Methods : From our prospectively maintained multi‐institutional registry across 4 comprehensive stroke centers, we identified patients with LVO AIS who underwent EVT requiring ≥ 3 passes to achieve successful reperfusion, defined as ≥ TICI 2b. Patient demographics, co‐morbidities, and severity of stroke based on NIHSS and ASPECTS were included within the analysis. Favorable outcome was defined as 90‐day post‐stroke modified Rankin Scale (mRS) 0–2. The primary outcomes were predictors of favorable outcome, which was assessed by multivariable logistic regression adjusted for age, baseline mRS, NIHSS, admission systolic and diastolic blood pressure, administration of tPA, number of passes during thrombectomy, history of hypertension, hyperlipidemia, atrial fibrillation, coronary artery disease, congestive heart failure, carotid stenosis, and diabetes. Results : Among 116 patients, median age was 70 (IQR 59–80), 48% were female, median NIHSS was 16.5 (IQR 13–22), and median number of passes was 3 (IQR 3–4, range 3–8). Patients with favorable outcome were younger (mean age 63±18.1 vs 70±14.5, favorable vs. non‐favorable, p = 0.041), and had lower NIHSS on presentation (mean 13.9±6.0 vs 18.3±7.4, favorable vs. non‐favorable p = 0.003). Patients with favorable outcome also had lower initial systolic blood pressure (149.6±32.8 vs 163.0±30.0 mmHg, favorable vs. non‐favorable, p = 0.047). In multivariable logistic regression adjusted for demographics and clinical characteristics, lower NIHSS was significantly associated with likelihood of good outcome (OR 0.88, 95% CI 0.81‐0.97, p = 0.009). Conclusions : Patients presenting with lower NIHSS are more likely to benefit from continued EVT attempts. These findings suggest that this population benefits from continued attempts at revascularization.

BackgroundWith the benefit of mechanical thrombectomy firmly established, the focus has shifted to improved delivery of care. Reducing time from symptom onset to reperfusion is a primary goal. Technology promises tremendous opportunities in the prehospital space to achieve this goal.MethodsThis review explores existing, fledgling, and potential future technologies for application in the prehospital space.ResultsThe opportunity for technology to improve stroke care resides in the detection, evaluation, triage, and transport of patients to an appropriate healthcare facility. Most prehospital technology remains in the early stages of design and implementation.ConclusionThe major challenges to tackle for future improvement in prehospital stroke care are that of public awareness, emergency medical service detection, and triage, and improved systems of stroke care. Thoughtfully applied technology will transform all these areas.

Glioblastoma (GBMs) is the most common and aggressive type of primary brain tumor in adults with dismal prognosis despite radical surgical resection coupled with chemo- and radiotherapy. Recent studies have proposed the use of small-molecule inhibitors, including verteporfin (VP), to target oncogenic networks in cancers. Here we report efficient encapsulation of water-insoluble VP in poly(lactic- co-glycolic acid) microparticles (PLGA MP) of ∼1.5 μm in diameter that allows tunable, sustained release. Treatment with naked VP and released VP from PLGA MP decreased cell viability of patient-derived primary GBM cells in vitro by ∼70%. Moreover, naked VP treatment significantly increased radiosensitivity of GBM cells, thereby enhancing overall tumor cell killing ability by nearly 85%. Our in vivo study demonstrated that two intratumoral administrations of sustained slow-releasing VP-loaded PLGA MPs separated by two weeks significantly attenuated tumor growth by ∼67% in tumor volume in a subcutaneous patient-derived GBM xenograft model over 26 d. Additionally, our in vitro data indicate broader utility of VP for treatment for other solid cancers, including chordoma, malignant meningioma, and various noncentral nervous system-derived carcinomas. Collectively, our work suggests that the use of VP-loaded PLGA MP may be an effective local therapeutic strategy for a variety of solid cancers, including unresectable and orphan tumors, which may decrease tumor burden and ultimately improve patient prognosis.

Early recurrence of cerebral ischemia in acutely symptomatic carotid artery stenosis can precede revascularization. The optimal antithrombotic regimen for this high-risk population is not well established. Although antiplatelet agents are commonly used, there is limited evidence for the use of anticoagulants. We sought to understand the safety and efficacy of short-term preoperative anticoagulants in secondary prevention of recurrent cerebral ischemic events from acutely symptomatic carotid stenosis in patients awaiting carotid endarterectomy (CEA).A retrospective query of a prospective single institution registry of carotid revascularization was performed. Patients who presented with acute ischemic stroke or transient ischemic attack (TIA) attributable to an ipsilateral internal carotid artery stenosis (ICA) were included. Antiplatelet (AP) only and anticoagulation (AC) treatment arms were compared. The primary outcome was a composite of preoperative recurrent ischemic stroke or TIA. The primary safety outcome was symptomatic intracranial hemorrhage.Out of 443 CEA patients, 342 were in the AC group and 101 in the AP group. Baseline characteristics between groups (AC vs AP) were similar apart from age (71±10.5 vs 73±9.5, p=0.04), premorbid modified Rankin scale (mRS) score (1.0±1.2 vs 1.4±1.3, p=0.03) and stroke as presenting symptom (65.8 vs 53.5%, p=0.02). Patients in the AC group had a lower incidence of recurrent stroke/TIA (3.8 vs 10.9%, p=0.006). One patient had symptomatic intracranial hemorrhage in the AC group, and none in the AP group. In multivariate analysis controlling for age, premorbid mRS, stroke severity, degree of stenosis, presence of intraluminal thrombus (ILT) and time to surgery, AC was protective (OR 0.30, p=0.007). This effect persisted in the cohort exclusively without ILT (OR 0.23, p=0.002).Short term preoperative anticoagulation in patients with acutely symptomatic carotid stenosis appears safe and effective compared to antiplatelet agents alone in the prevention of recurrent cerebral ischemic events while awaiting CEA.

Purpose: Reirradiation for recurrent glioma remains controversial without knowledge of optimal patient selection, dose, fractionation, and normal tissue tolerances. We retrospectively evaluated outcomes and toxicity after conventionally fractionated reirradiation for recurrent high-grade glioma, along with the impact of concurrent chemotherapy. Methods and materials: We conducted a retrospective review of patients reirradiated for high-grade glioma recurrence between 2007 and 2016 (including patients with initial low-grade glioma). Outcome metrics included overall survival (OS), prognostic factors for survival, and treatment-related toxicity. Results: Patients (n = 118; median age 47 years; median Karnofsky performance status score: 80) were re-treated at a median of 28 months (range, 5-214 months) after initial radiation therapy. The median reirradiation dose was 41.4 Gy (range, 12.6-54.0 Gy) to a median lesion volume of 202 cm3 (range, 20-901 cm3). The median cumulative (initial radiation and reirradiation combined) potential maximum brainstem dose was 76.9 Gy (range, 5.0-108.3 Gy) and optic apparatus dose was 56.0 Gy (range, 4.5-90.9 Gy). Of the patients, 56% received concurrent temozolomide, 14%, bevacizumab, and 11%, temozolomide plus bevacizumab; 19% had no chemotherapy. The planned reirradiation was completed by 90% of patients. Median OS from the completion of reirradiation was 9.6 months (95% confidence interval [CI], 7.5-11.7 months) for all patients and 14.0, 11.5, and 6.7 months for patients with initial grade 2, 3, and 4 glioma, respectively. On multivariate analysis, better OS was observed with a >24-month interval between radiation treatments (hazard ratio [HR]: 0.3; 95% CI, 0.2-0.5; P < .001), reirradiation dose >41.4 Gy (HR: 0.6; 95% CI, 0.4-0.9; P = .03), and gross total resection before reirradiation (HR: 0.6, 95% CI, 0.3-0.9; P = .02). Radiation necrosis and grade ≥3 late neurotoxicity were both minimal (41.4 Gy in conventional fractionation, along with chemotherapy, was safe and well tolerated with meaningful survival duration. These data provide information that may be useful in implementing safe reirradiation treatments for appropriately selected patients and guiding future studies to define optimal reirradiation doses, maximal safe doses to critical structures, and the role of systemic therapy.

Although lung adenocarcinomas frequently metastasize to the brain, treatment options for lung adenocarcinoma brain metastases are limited. We discovered novel candidate drivers of progression by using case-control analyses to compare whole-exome sequencing data from a cohort of 73 lung adenocarcinoma brain metastases to a control cohort of 503 primary lung adenocarcinomas. We identified 3 genomic regions with significantly more frequent amplifications in brain metastases compared to the control cohort: MYC (12% vs 6%), YAP1 (7% vs 0.8%) and MMP13 (10% vs 0.6%). We also identified CDKN2A/B as a region deleted at a significantly greater frequency in brain metastases compared to primary lung adenocarcinomas (27% vs 13%, respectively). We confirmed frequent amplifications of MYC and YAP1/MMP13 in an independent validation cohort of 105 lung adenocarcinoma brain metastasis samples using fluorescence in situ hybridization. We further validated that MYC, YAP1 and MMP13 can drive brain metastases in a patient-derived xenograft mouse model. We found a higher incidence of metastases to the brain in mice receiving intracardiac injections of tumor cells expressing the candidate drivers compared to tumor cells expressing LacZ as a control. These results indicate that somatic alterations can drive lung adenocarcinomas to metastasize to the brain. The candidate brain metastasis drivers that we identified may serve as therapeutic targets in patients with lung adenocarcinomas who develop this devastating complication.

Background The number needed to treat is a commonly used statistical term in modern neurointerventional practice. It represents the number of patients that need to be treated for one patient to benefit from an intervention. Given its growing popularity in reflecting study results, understanding the basics behind this statistic is of practical value to the neurointerventionalist. Methods Here, we review the basic theory and calculation of the number needed to treat, its application to stroke interventions, and its limitations. In addition, we demonstrate several simple methods of calculating the number needed to treat utilizing recent thrombectomy trial results. By presenting the number needed to treat as a universal metric, we provide a comprehensive comparative of the number needed to treat for key stroke therapies, including mechanical thrombectomy, tissue plasminogen activator, carotid endarterectomy, and prevention with antiplatelet and statin drugs. Conclusions In comparison with available stroke therapies, mechanical thrombectomy stands out as the most effective acute intervention in patients with emergent large-vessel occlusions. Understanding how the number needed to treat is derived and its implications helps provide perspective to clinical trial data, identify health-care resource priorities, and improve communication with patients, health-care providers, and additional key stakeholders.

SUMMARYUnderstanding the mechanisms controlling the invasive spread of normal and transformed cells is central to understanding diverse processes including cancer progression. Here, we report that Yes- associated protein (YAP), a central transcriptional regulator implicated in controlling organ and body size, modulates a Rho-GTPase switch that drives cellular migration by directly transactivating the Rac1-GEF protein TRIO. Additionally, YAP and TRIO activate the Rac1-STAT3 axis to promote invasive behavior. While we find this YAP-dependent infiltrative program in many cell types, it is particularly enhanced in a patient-specific way in the most common malignant brain tumor, glioblastoma (GBM), where hyperactivation of the YAP-mediated TRIO and STAT3 network also confers poor patient outcome and up-regulation of genes associated with the Mesenchymal subtype of GBM. Our analysis suggests that the YAP-TRIO-STAT3 signaling network identified in this study is a ubiquitous regulator of invasive cell spread in both normal and pathological contexts.

Although lung adenocarcinomas frequently metastasize to the brain, treatment options for lung adenocarcinoma brain metastases (BM-LUAD) are limited. We discovered novel candidate drivers of progression by using case-control analyses to compare whole-exome sequencing data from a cohort of 73 BM-LUAD to a control cohort of 503 primary lung adenocarcinomas. We identified MYC, YAP1 and MMP13 as genomic regions with significantly more frequent amplifications in BM-LUAD compared to control cohort. We validated that MYC, YAP1 and MMP13 can drive brain metastases in a patient-derived xenograft mouse model, where incidence of brain metastases was higher in mice injected with tumor cells expressing the candidate drivers compared to tumor cells expressing LacZ. These results indicate that somatic alterations can drive lung adenocarcinomas to metastasize to the brain. These candidate drivers may serve as therapeutic targets in patients with brain metastatic lung adenocarcinomas. Citation Format: Naema Nayyar, David J. Shih, Ivanna Bihun, Ibiayi Dagogo-Jack, Corey M. Gill, Elisa Aquilanti, Mia Bertalan, Alexander Kaplan, Megan R. D'Andrea, Ugonma Chukwueke, Christopher Alvarez-Breckenridge, Matthew Lastrapes, Ben Kuter, Matthew R. Strickland, Juan Carlos Martinez-Gutierrez, Deepika Nagabhushan, Magali De Sauvage, Michael D. White, Brandyn A. Castro, Kaitlin Hoang, Sun Ha Paek, Sun Hye Park, Maria Martinez-Lage, Anna S. Berghoff, Parker Merrill, Elizabeth R. Gerstner, Tracy T. Batchelor, Matthew P. Frosch, Ryan P. Frazier, Darrell R. Borger, A John Iafrate, Sandro Santagata, Matthias Preusser, Daniel P. Cahill, Scott L. Carter, Priscilla K. Brastianos. Identifying genomic drivers of lung adenocarcinoma brain metastases [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4729.

Summary: Molecular factors that define stem cell identity have recently emerged as oncogenic drivers. For instance, brachyury, a key developmental transcriptional factor, is also implicated in carcinogenesis, most notably of chordoma, through mechanisms that remain elusive. Here, we show that brachyury is a crucial regulator of stemness in chordoma and in more common aggressive cancers. Furthermore, this effect of brachyury is mediated by control of synthesis and stability of Yes-associated protein (YAP), a key regulator of tissue growth and homeostasis, providing an unexpected mechanism of control of YAP expression. We further demonstrate that the brachyury-YAP regulatory pathway is associated with tumor aggressiveness. These results elucidate a mechanism of controlling both tumor stemness and aggressiveness through regulatory coupling of two developmental factors. : Malignant neoplasms exhibit uninhibited and dysregulated growth coupled with acquisition of stem-like properties that are integral to the development and progression of disease. Shah et al. demonstrate a critical role of brachyury in regulating stemness and growth by activating YAP through direct transcriptional and post-transcriptional mechanisms in various cancers. Keywords: brachyury, YAP, chordoma, stremness, growth, glioblastoma, lung carcinoma

Patients with glioblastoma (GB) are known to have poor prognoses, and among these patients, those with poor neurological function have an even poorer prognosis. Consequently, aggressive surgeries and adjuvant therapies are often withheld because of this dismal outlook. The effects of aggressive therapies in this small subset of patients remain unknown. The goal of this study was to evaluate outcomes and factors associated with survival for poor functioning patients who underwent aggressive resection of their GB. Adult patients who underwent surgical resection of an intracranial primary GB at an academic tertiary-care institution between 1997 and 2007 were retrospectively reviewed. Patients with a Karnofsky Performance Scale (KPS) score of ≤60 were included. A total of 100 patients with primary GB met the inclusion criteria. The average age (±standard deviation) and KPS score of this cohort were 54 ± 15 years and 53 ± 12, respectively. No patient (0%) experienced perioperative mortality, and 0 (0%), 10 (10%), and 3 (3%) of patients incurred a new or increasing language, motor, and visual deficit, respectively. At last follow-up, 88 (88%) patients died with a median survival of 6.6 months. The factors associated with improved survival were age 2 cm (p = 0.01), radical tumor resection (p = 0.01), and temozolomide (p = 0.001). This study identifies a subset of patients with poor functional status who may benefit from aggressive surgical resection.

Determination of emm variations may help improve vaccine design., Group A Streptococcus (GAS) is a human-adapted pathogen that causes a variety of diseases, including pharyngitis and invasive infections. GAS strains are categorized by variation in the nucleotide sequence of the gene (emm) that encodes the M protein. To identify the emm types of GAS strains causing pharyngitis in Ontario, Canada, we sequenced the hypervariable region of the emm gene in 4,635 pharyngeal GAS isolates collected during 2002–2010. The most prevalent emm types varied little from year to year. In contrast, fine-scale geographic analysis identified inter-site variability in the most common emm types. Additionally, we observed fluctuations in yearly frequency of emm3 strains from pharyngitis patients that coincided with peaks of emm3 invasive infections. We also discovered a striking increase in frequency of emm89 strains among isolates from patients with pharyngitis and invasive disease. These findings about the epidemiology of GAS are potentially useful for vaccine research.

Many pathogens colonize different anatomical sites, but the selective pressures contributing to survival in the diverse niches are poorly understood. Group A Streptococcus (GAS) is a human-adapted bacterium that causes a range of infections. Much effort has been expended to dissect the molecular basis of invasive (sterile-site) infections, but little is known about the genomes of strains causing pharyngitis (streptococcal “sore throat”). Additionally, there is essentially nothing known about the genetic relationships between populations of invasive and pharyngitis strains. In particular, it is unclear if invasive strains represent a distinct genetic subpopulation of strains that cause pharyngitis. We compared the genomes of 86 serotype M3 GAS pharyngitis strains with those of 215 invasive M3 strains from the same geographical location. The pharyngitis and invasive groups were highly related to each other and had virtually identical phylogenetic structures, indicating they belong to the same genetic pool. Despite the overall high degree of genetic similarity, we discovered that strains from different host environments (i.e., throat, normally sterile sites) have distinct patterns of diversifying selection at the nucleotide level. In particular, the pattern of polymorphisms in the hyaluronic acid capsule synthesis operon was especially different between the two strain populations. This finding was mirrored by data obtained from full-genome analysis of strains sequentially cultured from nonhuman primates. Our results answer the long-standing question of the genetic relationship between GAS pharyngitis and invasive strains. The data provide previously undescribed information about the evolutionary history of pathogenic microbes that cause disease in different anatomical sites.

Understanding the fine-structure molecular architecture of bacterial epidemics has been a long-sought goal of infectious disease research. We used short-read-length DNA sequencing coupled with mass spectroscopy analysis of SNPs to study the molecular pathogenomics of three successive epidemics of invasive infections involving 344 serotype M3 group A Streptococcus in Ontario, Canada. Sequencing the genome of 95 strains from the three epidemics, coupled with analysis of 280 biallelic SNPs in all 344 strains, revealed an unexpectedly complex population structure composed of a dynamic mixture of distinct clonally related complexes. We discovered that each epidemic is dominated by micro- and macrobursts of multiple emergent clones, some with distinct strain genotype–patient phenotype relationships. On average, strains were differentiated from one another by only 49 SNPs and 11 insertion-deletion events (indels) in the core genome. Ten percent of SNPs are strain specific; that is, each strain has a unique genome sequence. We identified nonrandom temporal–spatial patterns of strain distribution within and between the epidemic peaks. The extensive full-genome data permitted us to identify genes with significantly increased rates of nonsynonymous (amino acid-altering) nucleotide polymorphisms, thereby providing clues about selective forces operative in the host. Comparative expression microarray analysis revealed that closely related strains differentiated by seemingly modest genetic changes can have significantly divergent transcriptomes. We conclude that enhanced understanding of bacterial epidemics requires a deep-sequencing, geographically centric, comparative pathogenomics strategy.

Trigeminal schwannomas represent between 0.07% and 0.36% of all intracranial tumors and 0.8% to 8% of intracranial schwannomas. Selection of the appropriate management strategy requires an understanding of the tumor's natural history and treatment outcomes. This report describes the case of a 36-year-old male who presented with a three-month history of progressive headaches, dizziness, loss of balance, decreased sleep, and cognitive decline. Magnetic resonance imaging revealed a large enhancing lesion centered around the left Meckel's cave and extending into both the middle and the posterior fossa with obstructive hydrocephalus secondary to compression of the fourth ventricle. Resection of the posterior fossa component of the tumor was performed in order to relieve the mass effect upon the brainstem without attempting a radical removal of the middle fossa component and a potential risk of further cognitive impairment. The pathological exam confirmed the diagnosis of a trigeminal schwannoma. The residual tumor showed progressive spontaneous volumetric shrinkage after a subtotal surgical resection. This case shows the value of a planned conservative surgery in complex schwannomas and highlights the challenges in interpreting the treatment responses in these benign tumors, whether approached surgically or with stereotactic radiation techniques.

Cancer cell migration is a critical process that underlies invasion, treatment evasion, and tumor recurrence. In the complex 3D-confined microenvironments of the body, a diverse molecular machinery drives migratory behavior. In particular, the recently discovered osmotic engine plays a pivotal role in promoting cell dispersal through directed water permeation. This osmotic engine machinery is driven by solute transporters and aquaporins, collectively named the transportome. Hence, it is imperative to determine the role of this transportome and its implications for invasive gliomas. Using novel in vitro microfluidic technology, we demonstrate for the first time that human glioblastoma (GBM) cells rely on the osmotic engine to migrate in confined microenvironments. In particular, using microchannel microfluidic devices, we characterize the migratory capacity of GBM cells in 3D-confined microenvironments using real-time imaging and assess their migratory behavior upon osmotic shock treatment. Our results show that GBM cells readily migrate in high degrees of confinement (3uM). In addition, when exposed to either a hypotonic shock at the leading edge or hypertonic shock at the lagging edge, these primary GBM cells reverse their directional migration, signifying the role of the osmotic engine model in brain cancer (p < 0.05). Furthermore, we uncover the transcription factor TEAD4 as a master regulator of the transportome gene signature and the osmotic engine collectively. Genetic inhibition of TEAD4 results in reduced migratory potential through confined microchannels as well as decreased speed within these confined spaces in vitro (p < 0.05). Using TCGA (n = 528) and REMBRANDT (n = 228) GBM patient datasets, we found that the TEAD4-controlled transportome machinery is overrepresented in glioblastomas and correlates with its poor prognosis. Taken together, our results show that the osmotic engine is a crucial mechanism for GBM cell migration driven by the TEAD4-dependent transportome machinery. Targeting this TEAD4-driven osmotic engine may hold a promising alternative for management of invasive gliomas.

Glioblastomas are characterized by their ability to disseminate into the local brain parenchyma; thus, confounding surgical excision and radiotherapy. Hence, it is imperative to identify and decipher the signaling networks that drive invasion. Glioblastoma cells utilize molecular transporters at both their leading (inward facing) and lagging (outward facing) edge to modulate cell volume and invade the confined microenvironment of the brain. These transporters include solute transporters as well as the aquaporins, and collectively behave as an osmotic engine for cellular invasion. However, the transcriptional regulators of these transporters have not been fully identified. Here, we report that TEAD4, a transcription factor implicated in neural development, is a potent regulator of the osmotic engine through transcriptional control of solute and water transporters. In particular, our data demonstrates that loss of TEAD4 decreases glioblastoma cells ability to migrate and invade through small pores (Boyden chamber and Matrigel transwell, respectively) mimicking the confined microenvironment of the brain (p < 0.05). Additionally, we uncover the role of TEAD4 in regulating members of the Na + /H+ exchanger, chloride co-transporter and aquaporin families, as well as the volume regulated anion channel to enable water permeation (p < 0.05). Apart from regulating cell dispersal, our data also shows that TEAD4 regulates glioblastoma proliferation (p < 0.05). Using the TCGA and REMBRANDT datasets, we observed TEAD4 is selectively overexpressed and hyperactive in glioblastomas compared to non-cancer cortex and lower grade gliomas (p < 0.05). Furthermore, we found that patients with elevated TEAD4 expression have a significantly shorter progression free survival and overall survival (p < 0.05). Taken together, our results show that TEAD4 is a potent regulator of cell dispersal through transcriptional control of the osmotic engine and has relevance to clinical outcomes of glioblastoma patients. Hence, TEAD4 may be a selective and potent therapeutic target that warrants further exploration.

Craniopharyngiomas are rare intracranial neoplasms that pose clinical challenges due to their location adjacent to vital structures. The authors have previously shown high mutation rates of BRAF V600E in papillary craniopharyngioma and of CTNNB1 in adamantinomatous craniopharyngioma. These activating driver mutations are potential therapeutic targets, and the authors have recently reported a significant response to BRAF/MEK inhibition in a patient with multiply recurrent PCP. As these targetable mutations warrant prospective research, the authors will be conducting a national National Cancer Institute–sponsored multicenter clinical trial to investigate BRAF/MEK inhibition in the treatment of craniopharyngioma. In this new era of genomic discovery, the treatment paradigm of craniopharyngioma is likely to change.

Glioblastoma (GBM) is a highly invasive and lethal brain tumor due to its high invasion and recurrence. The mechanisms that confer GBM cells their invasive behavior and their regulatory system have not been fully elucidated. We have shown that pharmacological inhibition and decreased expression of the electroneutral Na + -K + -Cl- cotransporter-1 (NKCC1) in GBM leads to a decreased cell migration and invasion capacity, in vitro and in vivo. We have previously reported that NKCC1 knockdown cells (NKCC1 KD) show significantly larger focal adhesions, suggesting a potential role of NKCC1 in cell adhesion. Here, we focused on the role of NKCC1 on the cytoskeleton dynamics of GBM cells. We found that glioma cells display a significant decrease on their cell spreading capacity upon NKCC1 knockdown or pharmacologic inhibition by Bumetanide (BMT) (p < 0.0001). F-actin staining showed a change in the organization of fibrillary actin of the cells, where NKCC1 KD cells displayed a ring shape actin morphology that was absent in control cells. In addition the bundled actin content was decreased by NKCC1 inhibition (GBM 612 p < 0.05; GBM 965 p < 0.001). The molecular regulation of actin dynamics can be due to the activity of RhoA acting through Cofilin, which acts as an initiator of actin polymerization. We observed that the small GTPase RhoA and Rac1 active levels decreased 40-50% in the NKCC1 KD cells. This result suggests that NKCC1 regulates cytoskeleton dynamics through multiple targets that include filament actin regulation and RhoA and Rac1 activity. Based on our results, NKCC1 modulates migration of GBM cells by at least two different mechanisms: cell volume regulation (through ion transport) and regulation of the actin cytoskeleton. Due to its essential role in cell migration and high expression in GBM, NKCC1 may serve as a specific therapeutic target to decrease GBM cell invasion.

Meningiomas frequently harbor inactivating mutations in the tumor suppressor protein Merlin (NF2), an upstream activator of the Hippo signaling pathway. This aberration drives tumor growth and aggressiveness through inactivation of this pathway and unchecked activation of its downstream effector, Yes-associated protein (YAP). The transcriptional coactivator YAP has been previously implicated in driving meningioma growth and malignant transformation of non-neoplastic arachnoid cells. YAP exerts its effect by direct binding to the TEAD family of transcription factors and transactivation of growth-related genes. However, the efficacy of pharmacologic modulation of this pathway in meningioma has yet to be explored. Verteporfin is a small molecule inhibitor of the porphyrin family, recently implicated as a direct inhibitor of YAP. Here, we report that Verteporfin modulates growth and radiation resistance in NF2 driven meningiomas through inhibition of the YAP-TEAD interaction. In particular, our data demonstrates that Verteporfin treatment in the NF2 mutant KT21MG1 human malignant meningioma cell line, results in a decreased activity of oncogenic YAP, resulting in decreased mRNA expression of YAP downstream targets (CTGF, Mcl-1 and ANKRD1) (p ≤ 0.05). Moreover, Verteporfin inhibits meningioma cell growth and proliferation in a dose dependent manner (MTT reduction and viable cell number) (p ≤ 0.05). Interestingly, pretreatment with Verteporfin results in increased sensitivity to irradiation in vitro (p ≤ 0.05). In addition, we explore the in vivo efficacy of Verteporfin treatment in a murine skull base xenograft model of human meningioma. Taken together, our results show that Verteporfin is a potent inhibitor of meningioma cell growth and radioresistance, making it an attractive drug candidate for treatment of this disease. Hence, this targeted therapy towards the NF2-YAP axis holds promising alternatives to current standard of care.