Inpatient Outcomes of Cerebral Venous Thrombosis in Patients With Malignancy Throughout the United States.

Background and Purpose: Cerebral venous thrombosis (CVT) is associated with a high degree of morbidity and mortality. Our objective is to elucidate characteristics, treatments, and outcomes of patients with cancer and CVT (CA-CVT). Methods: The 2016-2019 National Inpatient Sample (NIS) database was queried for patients with a primary diagnosis of CVT. Patients with a currently active diagnosis of malignancy (CA-CVT) were then identified. Demographics and comorbidities were compared between CA-CVT and CVT patients. Subgroup analyses explored patients with hematopoietic cancer and non-hematopoietic cancers. Stroke severity and treatment were explored. Inpatient outcomes studied were discharge disposition, length of stay, and mortality. Results: Between 2016 and 2019, 6,140 patients had a primary diagnosis code of CVT, and 370 (6.0%) patients had a coexisting malignancy. The most common malignancy was hematopoietic (n=195, 52.7%), followed by central nervous system (n=40, 10.8%), respiratory (n=40, 10.8%), and breast (n=40, 10.8%). These patients tended to be older than non-CA-CVT and were more likely to have coexisting comorbidities. CA-CVT patients had higher severity scores on the International Study of Cerebral Vein and Dural Sinus Thrombosis Risk Score (ISCVT-RS) and increased complications. In a propensity-score matched cohort, there were no differences in inpatient outcomes. Conclusion: Malignancy occurs in 6% of patients presenting with CVT and should be considered a potential comorbidity in instances where clear causes of hypercoagulabilty have not been identified. Malignancy was linked to higher mortality rates. Nonetheless, after adjusting for the severity of CVT, the outcomes for inpatients with cancer-associated CVT were comparable to those without cancer, indicating that the increased mortality associated with malignancy is probably due to more severe CVT conditions.

Central Nervous System Infections in Patients With Ventriculoperitoneal Shunts Admitted for Primary Abdominal Infections: A US Nationwide Cohort Analysis.

BACKGROUND AND OBJECTIVES: Although ventriculoperitoneal (VP) shunts are a common treatment for hydrocephalus, there are complication risks including infections. Late complications such as ventriculitis from ascending abdominal infections can have severe consequences. However, the incidence of central nervous system (CNS) infections in VP shunt patients with abdominal infections is not well understood. We aimed to determine the incidence of CNS infections in VP shunt patients admitted with abdominal infections. METHODS: Using the National Inpatient Sample, we studied patients from 2016 to 2019 to determine the incidence of CNS infections in VP shunt patients admitted with abdominal infections. Results were compared with VP shunt patients admitted for primary pneumonia. RESULTS: Among 725 VP shunt patients presenting with abdominal infections, 20 (2.8%) had CNS infections. Chronic obstructive pulmonary disease, hypertension, older age, and a smoking history were more common in patients with CNS infections and primary abdominal infection (P < .05). Patients who developed CNS infection had a significantly higher likelihood of both blood transfusion and coma but a lower likelihood of seizures. VP shunt patients with CNS infections were more likely to undergo shunt removal (odds ratio [OR] = 23.167, P < .001). 4.1% of VP shunt patients with primary abdominal infections died during admission. In a population of primary abdominal infection and pneumonia patients with VP shunts, a multivariate logistic regression analysis controlling for age, sex, and comorbidities identified abdominal infection as an independent risk factor for both CNS infection (OR = 51.208, P < .001) and inpatient death (OR = 3.417, P < .001). Among 6620 VP shunt patients admitted with primary pneumonia, only 5 (0.1%) had CNS infection compared with 20 (2.8%) in those with a primary abdominal infection (OR = 37.532, P < .001), and mortality was 1.6% vs 4.1% for those with a primary abdominal infection (P < .05). CONCLUSION: CNS infections in VP-shunted patients with abdominal infections are relatively rare but may lead to increased risks of death and other serious adverse outcomes.

What should otolaryngologists know about dural venous sinus stenting?

Dural venous sinus stenting is an emerging and exciting area in otolaryngology in collaboration with neurosurgeons and neuroradiologists. The first cases were reported 20 years ago. It is now considered part of the routine treatment of increased intracranial pressure due to transverse sinus stenosis. ENT doctors are the first to see these patients in their clinics, as sinus headaches, pulsating tinnitus, and dizziness are the most common symptoms. Previously, with limited success, high-dose diuretics and intracranial shunts had been the only options for treating these patients. Other methods, such as covering the sigmoid sinuses with graft material, appear to cause a sudden increase in intracranial pressure that can lead to blindness and even death. This overview summarizes the clinical and imaging characteristics of patients who will benefit from endovascular sinus stenting for elevated intracranial pressure.

Anticoagulation Use and Endovascular Thrombectomy in Patients with Large Core Stroke: A Secondary Analysis of the SELECT2 Trial.

Endovascular thrombectomy (EVT) safety and efficacy in patients with large core infarcts receiving oral anticoagulants (OAC) are unknown. In the SELECT2 trial (NCT03876457), 29 of 180 (16%; vitamin K antagonists 15, direct OACs 14) EVT, and 18 of 172 (10%; vitamin K antagonists 3, direct OACs 15) medical management (MM) patients reported OAC use at baseline. EVT was not associated with better clinical outcomes in the OAC group (EVT 6 [4-6] vs MM 5 [4-6], adjusted generalized odds ratio 0.89 [0.53-1.50]), but demonstrated significantly better outcomes in patients without OAC (EVT 4 [3-6] vs MM 5 [4-6], adjusted generalized odds ratio 1.87 [1.45-2.40], p = 0.02). The OAC group had higher comorbidities, including atrial fibrillation (70% vs 17%), congestive heart failure (28% vs 10%), and hypertension (87% vs 72%), suggesting increased frailty. However, the results were consistent after adjustment for these comorbidities, and was similar regardless of the type of OACs used. Whereas any hemorrhage rates were higher in the OAC group receiving EVT (86% in OAC vs 70% in no OAC), no parenchymal hemorrhage or symptomatic intracranial hemorrhage were observed with OAC use in both the EVT and MM arms. Although we did not find evidence that the effect was due to excess hemorrhage or confounded by underlying cardiac disease or older age, OAC use alone should not exclude patients from receiving EVT. Baseline comorbidities and ischemic injury extent should be considered while making individualized treatment decisions. ANN NEUROL 2024.

Acute kidney injury in subarachnoid hemorrhage: Exploring its clinical significance and prognostic implications.

OBJECTIVES: Subarachnoid hemorrhage (SAH) from spontaneous aneurysm rupture is a debilitating condition with high morbidity and mortality. Patients with SAH remain understudied, particularly concerning the evaluation of incidence and consequences of subsequent acute kidney injury (AKI). In this study, we aim to explore the risk factors and outcomes of AKI in SAH patients. MATERIALS AND METHODS: International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes were used to query the National Inpatient Sample (NIS) for patients with a diagnosis of SAH between 2010-2019. Subgroup analysis was stratified by AKI diagnosis during the same hospitalization. AKI and non-AKI groups were assessed for baseline clinical characteristics, interventions, complications, and outcomes. Descriptive statistics, multivariate regressions, and propensity score-matching were performed using IBM SPSS 28. RESULTS: Of 76,553 patients diagnosed with nontraumatic SAH between 2010-2019, 10,634 (13.89 %) had a comorbid diagnosis of AKI. SAH patients with AKI were older (p < 0.01) and more often obese (p < 0.01) compared to the non-AKI group. A multivariate regression found the diagnosis of AKI to be independently correlated with poor functional outcome (p < 0.001), above average length of stay (p < 0.001), and in-hospital mortality (p < 0.001) when controlling for age, SAH severity, and other comorbidities. CONCLUSIONS: This study showed significant association between AKI and adverse outcomes in SAH patients, and a correlation between AKI and heightened complication rates, poor functional outcome, extended hospital stays, and elevated mortality rates. Early detection of AKI in SAH patients is vital to improve their chances of recovery.

The Impact of Preprocedural Platelet Function Testing on Periprocedural Complication Rates Associated With Pipeline Flow Diversion: An International Multicenter Study.

BACKGROUND AND OBJECTIVES: Dual antiplatelet therapy (DAPT) is necessary to minimize the risk of periprocedural thromboembolic complications associated with aneurysm embolization using pipeline embolization device (PED). We aimed to assess the impact of platelet function testing (PFT) on reducing periprocedural thromboembolic complications associated with PED flow diversion in patients receiving aspirin and clopidogrel. METHODS: Patients with unruptured intracranial aneurysms requiring PED flow diversion were identified from 13 centers for retrospective evaluation. Clinical variables including the results of PFT before treatment, periprocedural DAPT regimen, and intracranial complications occurring within 72 h of embolization were identified. Complication rates were compared between PFT and non-PFT groups. Differences between groups were tested for statistical significance using the Wilcoxon rank sum, Fisher exact, or χ 2 tests. A P -value <.05 was statistically significant. RESULTS: 580 patients underwent PED embolization with 262 patients dichotomized to the PFT group and 318 patients to the non-PFT group. 13.7% of PFT group patients were clopidogrel nonresponders requiring changes in their pre-embolization DAPT regimen. Five percentage of PFT group [2.8%, 8.5%] patients experienced thromboembolic complications vs 1.6% of patients in the non-PFT group [0.6%, 3.8%] ( P = .019). Two (15.4%) PFT group patients with thromboembolic complications experienced permanent neurological disability vs 4 (80%) non-PFT group patients. 3.7% of PFT group patients [1.5%, 8.2%] and 3.5% [1.8%, 6.3%] of non-PFT group patients experienced hemorrhagic intracranial complications ( P > .9). CONCLUSION: Preprocedural PFT before PED treatment of intracranial aneurysms in patients premedicated with an aspirin and clopidogrel DAPT regimen may not be necessary to significantly reduce the risk of procedure-related intracranial complications.

Treatment trends and clinical outcomes of endovascular embolization for unruptured intracranial aneurysms in the pediatric population.

BACKGROUND: Owing to the relative rarity of unruptured intracranial aneurysms (UIAs) in the pediatric population, evidence regarding treatment modalities and clinical outcomes remains limited. OBJECTIVE: To characterize the use and clinical outcomes of endovascular therapy (EVT) and microsurgical clipping (MSC) for pediatric UIAs over a two-decade interval using a large national registry. METHODS: Pediatric (<18 years of age) UIA hospitalizations were identified in the National Inpatient Sample from 2002 to 2019. Temporal use and clinical outcomes were compared for treatment with EVT and MSC. RESULTS: Among 734 UIAs identified, 64.9% (n=476) were treated with EVT. Use of EVT significantly increased during the study period from 54.3% (2002-2004) to 78.6% (2017-2019) (P=0.002 by Cochrane-Armitage test). In comparison with those treated with MSC, pediatric patients treated with EVT demonstrated higher rates of favorable outcomes (discharge to home without services) (96.0% vs 91.1%, P=0.006), shorter durations of hospital stay (4.6 vs 10.0 days, P<0.001), and lower rates of ischemic or hemorrhagic procedural-related complications (1% vs 4%, P=0.010). Conservative management also increased significantly over the study period (P<0.001 by Cochrane-Armitage test). CONCLUSION: A retrospective evaluation of nearly 20 years of population-level data from the United States demonstrates increasing use of EVT for the treatment of pediatric UIAs, with high rates of favorable outcomes and shorter hospital stays in comparison with those treated with microsurgery.

Endovascular thrombectomy for treatment of isolated posterior cerebral artery occlusion: a real-world analysis of hospitalizations in the United States.

BACKGROUND: Despite renewed interest and recently demonstrated efficacy for endovascular thrombectomy (EVT) for treatment of acute ischemic stroke (AIS) of the posterior circulation, to date, no randomized clinical trials have been conducted to evaluate EVT for isolated occlusions of the posterior cerebral artery (IPCA). METHODS: Hospitalizations for adult patients with primary admission diagnoses of IPCA occlusion were identified in the National Inpatient Sample registry during the period of 2016-2020. The study exposure was treatment with EVT, and primary clinical endpoints included favorable functional outcome (defined as discharge disposition to home without services, previously shown to have high concordance with modified Rankin scale scores 0-2), in-hospital mortality, and any intracranial hemorrhage (ICH). Inverse probability of treatment weighting (IPTW) was performed to balance baseline clinical characteristics between those receiving EVT or medical management (MM). RESULTS: This analysis identified 34,880 IPCA occlusion hospitalizations, 730 (2.1%) of which documented treatment with EVT. Following IPTW adjustment, EVT was associated with favorable outcome in IPCA patients presenting with mild deficits (M-D) (NIHSS < 6) [adjusted odds ratio (aOR) 2.36, 95% confidence interval (CI) 2.27, 2.45; p < 0.001] and in those presenting with moderate-to-severe deficits (M-S-D) (NIHSS 6-42) (aOR 2.00, 95% CI 1.86, 2.15; p < 0.001). Mortality rates did not differ among those with M-S-D [EVT 4.8% vs. MM 4.7%, p = 0.742], while ICH rates were lower. CONCLUSION: Retrospective analysis of a large administrative registry in the Unites States demonstrates an association of EVT with favorable outcomes following IPCA occlusion, without concomitant risk of hemorrhagic transformation or mortality.

Endovascular thrombectomy for large ischemic strokes: An updated living systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Recent studies indicate endovascular thrombectomy (EVT) as a safe, effective treatment for acute ischemic stroke (AIS) with large ischemic regions. Our study updates an ongoing living systematic review and meta-analysis of randomized controlled trials (RCTs) comparing outcomes of EVT to medical management only. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Library for RCTs comparing EVT to medical management in AIS patients with large ischemic areas. Using fixed-effect models, we conducted a meta-analysis to compare functional independence, mortality, and symptomatic intracranial hemorrhage (sICH) between EVT and standard medical management. We evaluated bias risk with the Cochrane tool and graded the certainty of evidence using the GRADE approach. RESULTS: Of 1363 new citations, we included six RCTs with a total of 1876 patients. We found low-certainty evidence of improved functional independence (risk difference [RD] 29.9%, 95% CI 17.2% to 46.9%), increase in sICH (RD 2.6%, 95% CI 0.3% to 6.4%), and a non-significant decrease in mortality (RD -1.8%, 95% CI -3.9% to 0.6%) for AIS patients with large infarcts who underwent EVT compared to medical management only. CONCLUSION: Our revised meta-analysis suggests low-certainty evidence that there is improved functional independence, a non-significant decrease in mortality, and an increase in sICH among AIS patients with large infarcts who undergo EVT compared to those receiving medical management alone. SYSTEMATIC REVIEW PROTOCOL REGISTRATION: PROSPERO (CRD42023398742).

Outcomes of heparin-induced thrombocytopenia type II in aneurysmal subarachnoid hemorrhage patients: A US nationwide analysis.

BACKGROUND: Despite the widespread use of heparin during and following endovascular procedures in the management of aneurysmal subarachnoid hemorrhage (SAH) patients, limited research has explored the incidence and impact of heparin-induced thrombocytopenia (HIT) on SAH. METHODS: Descriptive statistics, multivariate regressions, and propensity score-matching were employed to compare clinical characteristics, comorbidities, interventions, complications, and outcomes of HIT in SAH patients identified within the US National Inpatient Sample database from 2010 to 2019. RESULTS: Among 76 387 SAH patients from 2010 to 2019, 166 (0.22%) developed HIT. HIT was identified as a significant predictor of prolonged length of stay (OR 6.799, 95% CI 3.985 to 11.6, P<0.01) and poor functional outcomes (OR 2.541, 95% CI 1.628 to 3.966, P<0.01) after adjusting for relevant factors. HIT incidence was higher in patients with elevated SAH severity scores (1.42 vs 1.06, P<0.01), younger patients (58.04 vs 61.39 years, P=0.01), overweight individuals (0.4% vs 0.2%, P<0.01), those on long-term anticoagulants (10.84% vs 5.72%, P<0.01), or with a cerebrospinal fluid drainage device (external ventricular drain, ventriculoperitoneal shunt; P<0.01). HIT patients showed increased rates of endovascular coiling, ventricular drain placement, shunt placement, deep vein thrombosis, urinary tract infection, acute kidney injury, pulmonary embolism, venous sinus thrombosis, pneumonia, and cerebral vasospasm (all P<0.01). CONCLUSION: SAH patients with HIT exhibited various comorbidities and increased rates of complications, which may contribute to extended hospital stays. This nationwide study aids clinical suspicion and highlights HIT's impact on SAH patients.

Clinical relevance of intracranial hemorrhage after thrombectomy versus medical management for large core infarct: a secondary analysis of the SELECT2 randomized trial.

BACKGROUND: The incidence of intracerebral hemorrhage (ICH) and its effect on the outcomes after endovascular thrombectomy (EVT) for patients with large core infarcts have not been well-characterized. METHODS: SELECT2 trial follow-up imaging was evaluated using the Heidelberg Bleeding Classification (HBC) to define hemorrhage grade. The association of ICH with clinical outcomes and treatment effect was examined. RESULTS: Of 351 included patients, 194 (55%) and 189 (54%) demonstrated intracranial and intracerebral hemorrhage, respectively, with a higher incidence in EVT (134 (75%) and 130 (73%)) versus medical management (MM) (60 (35%) and 59 (34%), both P<0.001). Hemorrhagic infarction type 1 (HBC=1a) and type 2 (HBC=1b) accounted for 93% of all hemorrhages. Parenchymal hematoma (PH) type 1 (HBC=1c) and type 2 (HBC=2) were observed in 1 (0.6%) EVT-treated and 4 (2.2%) MM patients. Symptomatic ICH (sICH) (SITS-MOST definition) was seen in 0.6% EVT patients and 1.2% MM patients. No trend for ICH with core volumes (P=0.10) or Alberta Stroke Program Early CT Score (ASPECTS) (P=0.74) was observed. Among EVT patients, the presence of any ICH did not worsen clinical outcome (modified Rankin Scale (mRS) at 90 days: 4 (3-6) vs 4 (3-6); adjusted generalized OR 1.00, 95% CI 0.68 to 1.47, P>0.99) or modify EVT treatment effect (Pinteraction=0.77). CONCLUSIONS: ICH was present in 75% of the EVT population, but PH or sICH were infrequent. The presence of any ICH did not worsen functional outcomes or modify EVT treatment effect at 90-day follow-up. The high rate of hemorrhages overall still represents an opportunity for adjunctive therapies in EVT patients with a large ischemic core.

Ultra-Early Hemostatic Therapy for Acute Intracerebral Hemorrhage: An Updated Review.

Intracerebral hemorrhage (ICH) is the second most common type of stroke, accounting for approximately 10-20% of all strokes, and is linked to severe neurological disability and death. Since the most accurate predictor of outcome in patients with ICH is hematoma volume, there is a great need for pharmacologic therapy that can reduce hematoma expansion and resultant mass effect and edema. This is especially critical within the ultra-early window of 3-4 hours after the presentation. Hemostatic therapies are exceptionally important for those patients taking antiplatelet or anticoagulant medications to reverse the effects of these medications and therefore prevent hematoma expansion. Furthermore, the recent publication of the 2023 Guideline for the Management of Patients with Aneurysmal Subarachnoid Hemorrhage by the American Heart Association/American Stroke Association, the first update to the guidelines since 2012, underscores the importance of optimizing anticoagulation reversal for this population. The purpose of this selective, nonsystematic review is to examine current literature regarding the use of hemostatic therapies in ICH, with particular attention paid to antiplatelet, anticoagulation, and antifibrinolytic therapies.

Outcomes of acute ischemic stroke among patients with renal cell carcinoma: A nationwide analysis.

INTRODUCTION: Renal cell carcinoma (RCC) has been associated with an increased risk for acute ischemic stroke (AIS). As individuals with cancer who experience AIS tend to face higher mortality rates compared to AIS patients without cancer, recognizing the implications of RCC in AIS is crucial for identifying high-risk patients for major complications and directing management strategies. OBJECTIVE: To examine risk factors, interventions, and outcomes for patients with AIS stratified by their RCC diagnosis. METHODS: The National Inpatient Sample (NIS) database was queried for the period 2010-2019 using International Classification of Disease 10th Edition (ICD-10) codes for acute ischemic stroke and renal malignancies. We assessed demographic information, comorbidities, and clinical interventions between patients presenting with AIS, with and without renal malignancies. A logistic regression model was employed to further examine mortality outcomes. RESULTS: Among 1,609,817 patients identified with AIS, 2,068 (0.12%) had a concomitant diagnosis of RCC. AIS patients with RCC were older (72.09 yrs. vs. 70.9 yrs., p < 0.01), more often white (72.05% vs. 68.16%, p < 0.01), and had similar stroke severity scores. RCC patients received less tissue plasminogen activator (tPA; 4.98% vs. 6.2%, p = 0.02) but underwent endovascular mechanical thrombectomy (MT) at similar rates. RCC patients had more complications (p < 0.01) as well as longer hospital stays (8.19 days vs. 5.98 days, p < 0.01), and higher rates of mortality (11.27% vs. 5.63%, p < 0.01), when compared to their non-RCC counterparts. Propensity score-adjusted analysis largely confirmed these findings, with RCC being positively associated with in-hospital mortality (OR: 1.373, p < 0.01) and longer stays (OR: 2.591, p < 0.01). CONCLUSION: In addition to describing the demographics and clinical course of AIS patients diagnosed with RCC, our study underscores the substantial impact of RCC on AIS outcomes. Despite experiencing strokes of similar severity, AIS patients diagnosed with RCC are at a heightened risk of complications, including thromboembolic events and infections, leading to elevated in-hospital mortality rates and prolonged hospital stays.

Discrete Mechanistic Target of Rapamycin Signaling Pathways, Stem Cells, and Therapeutic Targets.

The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions via its discrete binding partners to form two multiprotein complexes, mTOR complex 1 and 2 (mTORC1 and mTORC2). Rapamycin-sensitive mTORC1, which regulates protein synthesis and cell growth, is tightly controlled by PI3K/Akt and is nutrient-/growth factor-sensitive. In the brain, mTORC1 is also sensitive to neurotransmitter signaling. mTORC2, which is modulated by growth factor signaling, is associated with ribosomes and is insensitive to rapamycin. mTOR regulates stem cell and cancer stem cell characteristics. Aberrant Akt/mTOR activation is involved in multistep tumorigenesis in a variety of cancers, thereby suggesting that the inhibition of mTOR may have therapeutic potential. Rapamycin and its analogues, known as rapalogues, suppress mTOR activity through an allosteric mechanism that only suppresses mTORC1, albeit incompletely. ATP-catalytic binding site inhibitors are designed to inhibit both complexes. This review describes the regulation of mTOR and the targeting of its complexes in the treatment of cancers, such as glioblastoma, and their stem cells.

Endovascular thrombectomy plus medical care versus medical care alone for large ischaemic stroke: 1-year outcomes of the SELECT2 trial.

BACKGROUND: Multiple randomised trials have shown efficacy and safety of endovascular thrombectomy in patients with large ischaemic stroke. The aim of this study was to evaluate long-term (ie, at 1 year) evidence of benefit of thrombectomy for these patients. METHODS: SELECT2 was a phase 3, open-label, international, randomised controlled trial with blinded endpoint assessment, conducted at 31 hospitals in the USA, Canada, Spain, Switzerland, Australia, and New Zealand. Patients aged 18-85 years with ischaemic stroke due to proximal occlusion of the internal carotid artery or of the first segment of the middle cerebral artery, showing large ischaemic core on non-contrast CT (Alberta Stroke Program Early Computed Tomographic Score of 3-5 [range 0-10, with lower values indicating larger infarctions]) or measuring 50 mL or more on CT perfusion and MRI, were randomly assigned, within 24 h of ischaemic stroke onset, to thrombectomy plus medical care or to medical care alone. The primary outcome for this analysis was the ordinal modified Rankin Scale (range 0-6, with higher scores indicating greater disability) at 1-year follow-up in an intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT03876457) and is completed. FINDINGS: The trial was terminated early for efficacy at the 90-day follow-up after 352 patients had been randomly assigned (178 to thrombectomy and 174 to medical care only) between Oct 11, 2019, and Sept 9, 2022. Thrombectomy significantly improved the 1-year modified Rankin Scale score distribution versus medical care alone (Wilcoxon-Mann-Whitney probability of superiority 0·59 [95% CI 0·53-0·64]; p=0·0019; generalised odds ratio 1·43 [95% CI 1·14-1·78]). At the 1-year follow-up, 77 (45%) of 170 patients receiving thrombectomy had died, compared with 83 (52%) of 159 patients receiving medical care only (1-year mortality relative risk 0·89 [95% CI 0·71-1·11]). INTERPRETATION: In patients with ischaemic stroke due to a proximal occlusion and large core, thrombectomy plus medical care provided a significant functional outcome benefit compared with medical care alone at 1-year follow-up. FUNDING: Stryker Neurovascular.

Endovascular Thrombectomy for Large Ischemic Stroke Across Ischemic Injury and Penumbra Profiles.

Importance: Whether endovascular thrombectomy (EVT) efficacy for patients with acute ischemic stroke and large cores varies depending on the extent of ischemic injury is uncertain. Objective: To describe the relationship between imaging estimates of irreversibly injured brain (core) and at-risk regions (mismatch) and clinical outcomes and EVT treatment effect. Design, Setting, and Participants: An exploratory analysis of the SELECT2 trial, which randomized 352 adults (18-85 years) with acute ischemic stroke due to occlusion of the internal carotid or middle cerebral artery (M1 segment) and large ischemic core to EVT vs medical management (MM), across 31 global centers between October 2019 and September 2022. Intervention: EVT vs MM. Main Outcomes and Measures: Primary outcome was functional outcome-90-day mRS score (0, no symptoms, to 6, death) assessed by adjusted generalized OR (aGenOR; values >1 represent more favorable outcomes). Benefit of EVT vs MM was assessed across levels of ischemic injury defined by noncontrast CT using ASPECTS score and by the volume of brain with severely reduced blood flow on CT perfusion or restricted diffusion on MRI. Results: Among 352 patients randomized, 336 were analyzed (median age, 67 years; 139 [41.4%] female); of these, 168 (50%) were randomized to EVT, and 2 additional crossover MM patients received EVT. In an ordinal analysis of mRS at 90 days, EVT improved functional outcomes compared with MM within ASPECTS categories of 3 (aGenOR, 1.71 [95% CI, 1.04-2.81]), 4 (aGenOR, 2.01 [95% CI, 1.19-3.40]), and 5 (aGenOR, 1.85 [95% CI, 1.22-2.79]). Across strata for CT perfusion/MRI ischemic core volumes, aGenOR for EVT vs MM was 1.63 (95% CI, 1.23-2.16) for volumes ≥70 mL, 1.41 (95% CI, 0.99-2.02) for ≥100 mL, and 1.47 (95% CI, 0.84-2.56) for ≥150 mL. In the EVT group, outcomes worsened as ASPECTS decreased (aGenOR, 0.91 [95% CI, 0.82-1.00] per 1-point decrease) and as CT perfusion/MRI ischemic core volume increased (aGenOR, 0.92 [95% CI, 0.89-0.95] per 10-mL increase). No heterogeneity of EVT treatment effect was observed with or without mismatch, although few patients without mismatch were enrolled. Conclusion and Relevance: In this exploratory analysis of a randomized clinical trial of patients with extensive ischemic stroke, EVT improved clinical outcomes across a wide spectrum of infarct volumes, although enrollment of patients with minimal penumbra volume was low. In EVT-treated patients, clinical outcomes worsened as presenting ischemic injury estimates increased. Trial Registration: ClinicalTrials.gov Identifier: NCT03876457.

Endovascular Thrombectomy Treatment Effect in Direct vs Transferred Patients With Large Ischemic Strokes: A Prespecified Analysis of the SELECT2 Trial.

Importance: Patients with large ischemic core stroke have poor clinical outcomes and are frequently not considered for interfacility transfer for endovascular thrombectomy (EVT). Objective: To assess EVT treatment effects in transferred vs directly presenting patients and to evaluate the association between transfer times and neuroimaging changes with EVT clinical outcomes. Design, Setting, and Participants: This prespecified secondary analysis of the SELECT2 trial, which evaluated EVT vs medical management (MM) in patients with large ischemic stroke, evaluated adults aged 18 to 85 years with acute ischemic stroke due to occlusion of the internal carotid or middle cerebral artery (M1 segment) as well as an Alberta Stroke Program Early CT Score (ASPECTS) of 3 to 5, core of 50 mL or greater on imaging, or both. Patients were enrolled between October 2019 and September 2022 from 31 EVT-capable centers in the US, Canada, Europe, Australia, and New Zealand. Data were analyzed from August 2023 to January 2024. Interventions: EVT vs MM. Main Outcomes and Measures: Functional outcome, defined as modified Rankin Scale (mRS) score at 90 days with blinded adjudication. Results: A total of 958 patients were screened and 606 patients were excluded. Of 352 enrolled patients, 145 (41.2%) were female, and the median (IQR) age was 66.5 (58-75) years. A total of 211 patients (59.9%) were transfers, while 141 (40.1%) presented directly. The median (IQR) transfer time was 178 (136-230) minutes. The median (IQR) ASPECTS decreased from the referring hospital (5 [4-7]) to an EVT-capable center (4 [3-5]). Thrombectomy treatment effect was observed in both directly presenting patients (adjusted generalized odds ratio [OR], 2.01; 95% CI, 1.42-2.86) and transferred patients (adjusted generalized OR, 1.50; 95% CI, 1.11-2.03) without heterogeneity (P for interaction = .14). Treatment effect point estimates favored EVT among 82 transferred patients with a referral hospital ASPECTS of 5 or less (44 received EVT; adjusted generalized OR, 1.52; 95% CI, 0.89-2.58). ASPECTS loss was associated with numerically worse EVT outcomes (adjusted generalized OR per 1-ASPECTS point loss, 0.89; 95% CI, 0.77-1.02). EVT treatment effect estimates were lower in patients with transfer times of 3 hours or more (adjusted generalized OR, 1.15; 95% CI, 0.73-1.80). Conclusions and Relevance: Both directly presenting and transferred patients with large ischemic stroke in the SELECT2 trial benefited from EVT, including those with low ASPECTS at referring hospitals. However, the association of EVT with better functional outcomes was numerically better in patients presenting directly to EVT-capable centers. Prolonged transfer times and evolution of ischemic change were associated with worse EVT outcomes. These findings emphasize the need for rapid identification of patients suitable for transfer and expedited transport. Trial Registration: ClinicalTrials.gov Identifier: NCT03876457.

Mapping geographic disparities in treatment and clinical outcomes of high-grade aneurysmal subarachnoid hemorrhage in the United States.

BACKGROUND AND OBJECTIVE: Although high-grade (Hunt and Hess 4 and 5) aneurysmal subarachnoid hemorrhage (aSAH) typically portends a poor prognosis, early and aggressive treatment has previously been demonstrated to confer a significant survival advantage. This study aims to evaluate geographic, demographic, and socioeconomic determinants of high-grade aSAH treatment in the United States. METHODS: The National Inpatient Sample (NIS) was queried to identify adult high-grade aSAH hospitalizations during the period of 2015 to 2019 using the International Classification of Diseases, 10th Revision, Clinical Modification (ICD) codes. The primary clinical endpoint of this analysis was aneurysm treatment by surgical or endovascular intervention (SEI), while the exposure of interest was geographic region by census division. Favorable functional outcome (assessed by the dichotomous NIS-SAH Outcome Measure, or NIS-SOM) and in-hospital mortality were evaluated as secondary endpoints in treated and conservatively managed groups. RESULTS: Among 99 460 aSAH patients identified, 36 795 (37.0%) were high-grade, and 9210 (25.0%) of these were treated by SEI. Following multivariable logistic regression analysis, determinants of treatment by SEI included female sex (adjusted OR (aOR) 1.42, 95% CI 1.35 to 1.51), transfer admission (aOR 1.18, 95% CI 1.12 to 1.25), private insurance (ref: government-sponsored insurance) (aOR 1.21, 95% CI 1.14 to 1.28), and government hospital ownership (ref: private ownership) (aOR 1.17, 95% CI 1.09 to 1.25), while increasing age (by decade) (aOR 0.93, 95% CI 0.91 to 0.95), increasing mortality risk (aOR 0.60, 95% CI 0.57 to 0.63), urban non-teaching hospital status (aOR 0.66, 95% CI 0.59 to 0.73), rural hospital location (aOR 0.13, 95% CI 0.7 to 0.25), small hospital bedsize (aOR 0.68, 95% CI 0.60 to 0.76), and geographic region (South Atlantic (aOR 0.72, 95% CI 0.63 to 0.83), East South Central (aOR 0.75, 95% CI 0.64 to 0.88), and Mountain (aOR 0.72, 95% CI 0.61 to 0.85)) were associated with a lower likelihood of treatment. High-grade aSAH patients treated by SEI experienced significantly greater rates of favorable functional outcomes (20.1% vs 17.3%; OR 1.20, 95% CI 1.13 to 1.28, P<0.001) and lower rates of mortality (25.8% vs 49.1%; OR 0.36, 95% CI 0.34 to 0.38, P<0.001) in comparison to those conservatively managed. CONCLUSION: A complex interplay of demographic, socioeconomic, and geographic factors influence treatment patterns of high-grade aSAH in the United States.

Brain Metastases Are Regulated by Immuno-inflammatory Signaling Pathways Governed by STAT3, MAPK and Tumor Suppressor p53 Status: Possible Therapeutic Targets.

BACKGROUND/AIM: Brain metastasis (BM) is a complex multi-step process involving various immune checkpoint proteins. Mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1/2 (ERK1/2), and signal transducer and activator of transcription 3 (STAT3) are implicated in tumorigenesis and are critical upstream regulators of Programmed Death Ligand 1 (PD-L1), an immunotherapy target. Tumor suppressor p53, dysregulated in cancers, regulates STAT3 and ERK1/2 signaling. This study examined the roles of STAT3, MAPK and p53 status in BM initiation and maintenance. MATERIALS AND METHODS: Twenty-six BM, with various primary malignancies, were used (IRB-approved) to determine mutant p53 (p53mt), pSTAT3Tyr705, pERK1/2Thr202/Tyr204, and PD-L1 expression using immunohistochemistry. cDNA microarray was used for gene expression analysis. Brain-metastatic breast cancer cells (MDA-MB-231) were treated with STAT3 (NSC74859) or MAPK/ERK1/2 (U0126) inhibitors in regular or astrocytic media. ERK1/2 pathway was assessed using western blotting, and cell proliferation and migration were determined using MTT and scratch-wound assays, respectively. RESULTS: pSTAT3Tyr705 and pERK1/2Thr202/Tyr204 were expressed at tumor margins, whereas p53mt and PD-L1 were uniformly expressed, with significant overlap between expression of these proteins. Gene expression analysis identified alterations in 18 p53- and 32 STAT3- or MAPK-associated genes contributing to dysregulated immune responses and cell cycle regulation. U0126 and NSC74859 reduced pERK1/2Thr202/Tyr204 expression. Cell proliferation decreased following each treatment (p≤0.01). Migration stagnated following U0126 treatment in astrocytic media (p≤0.01). CONCLUSION: Activation of STAT3 and ERK1/2 promotes BM and provides compelling evidence for use of STAT3, ERK1/2 and p53 status as potential immunotherapeutic targets in BM.