Cancer-Associated Stroke: Thrombosis Mechanism, Diagnosis, Outcome, and Therapeutic Strategies.

Cancer can induce hypercoagulability, which may lead to stroke. This occurs when tumor cells activate platelets as part of their growth and metastasis. Tumor cells activate platelets by generating thrombin and expressing tissue factor, resulting in tumor cell-induced platelet aggregation. Histopathological studies of thrombi obtained during endovascular thrombectomy in patients with acute stroke and active cancer have shown a high proportion of platelets and thrombin. This underscores the crucial roles of platelets and thrombin in cancer-associated thrombosis. Cancer-associated stroke typically occurs in patients with active cancer and is characterized by distinctive features. These features include multiple infarctions across multiple vascular territories, markedly elevated blood D-dimer levels, and metastasis. The presence of cardiac vegetations on echocardiography is a robust indicator of cancer-associated stroke. Suspicion of cancer-associated stroke during endovascular thrombectomy arises when white thrombi are detected, particularly in patients with active cancer. Cancer-associated stroke is almost certain when histopathological examination of thrombi shows a very high platelet and a very low erythrocyte composition. Patients with cancer-associated stroke have high risks of mortality and recurrent stroke. However, limited data are available on the optimal treatment regimen for stroke prevention in these patients. Thrombosis mechanism in cancer is well understood, and distinct therapeutic targets involving thrombin and platelets have been identified. Therefore, direct thrombin inhibitors and/or antiplatelet agents may effectively prevent stroke recurrence. Additionally, this strategy has potential benefits in cancer treatment as accumulating evidence suggests that aspirin use reduces cancer progression, metastasis, and cancer-related mortality. However, clinical trials are necessary to assess the efficacy of this strategy involving the use of direct thrombin inhibitors and/or antiplatelet therapies.

Effectiveness of endovascular treatment for in-hospital stroke vs. community-onset stroke: a propensity score-matched analysis.

BACKGROUND: The effectiveness of endovascular treatment for in-hospital stroke remains debatable. We aimed to compare the outcomes between patients with in-hospital stroke and community-onset stroke who received endovascular treatment. METHODS: This prospective registry-based cohort study included consecutive patients who underwent endovascular treatment from January 2013 to December 2022 and were registered in the Selection Criteria in Endovascular Thrombectomy and Thrombolytic Therapy study and Yonsei Stroke Cohort. Functional outcomes at day 90, radiological outcomes, and safety outcomes were compared between the in-hospital and community-onset groups using logistic regression and propensity score-matched analysis. RESULTS: Of 1,219 patients who underwent endovascular treatment, 117 (9.6%) had in-hospital stroke. Patients with in-hospital onset were more likely to have a pre-stroke disability and active cancer than those with community-onset. The interval from the last known well to puncture was shorter in the in-hospital group than in the community-onset group (155 vs. 355 min, p<0.001). No significant differences in successful recanalization or safety outcomes were observed between the groups; however, the in-hospital group exhibited worse functional outcomes and higher mortality at day 90 than the community-onset group (all p<0.05). After propensity score matching including baseline characteristics, functional outcomes after endovascular treatment did not differ between the groups (OR: 1.19, 95% CI 0.78-1.83, p=0.4). Safety outcomes did not significantly differ between the groups. CONCLUSION: Endovascular treatment is a safe and effective treatment for eligible patients with in-hospital stroke. Our results will help physicians in making decisions when planning treatment and counseling caregivers or patients.

Identification of acute myocardial infarction and stroke events using the National Health Insurance Service database in Korea.

OBJECTIVES: The escalating burden of cardiovascular disease (CVD) is a critical public health issue worldwide. CVD, especially acute myocardial infarction (AMI) and stroke, is the leading contributor to morbidity and mortality in Korea. We aimed to develop algorithms for identifying AMI and stroke events from the National Health Insurance Service (NHIS) database and validate these algorithms through medical record review. METHODS: We first established a concept and definition of "hospitalization episode," taking into account the unique features of health claims-based NHIS database. We then developed first and recurrent event identification algorithms, separately for AMI and stroke, to determine whether each hospitalization episode represents a true incident case of AMI or stroke. Finally, we assessed our algorithms' accuracy by calculating their positive predictive values (PPVs) based on medical records of algorithm- identified events. RESULTS: We developed identification algorithms for both AMI and stroke. To validate them, we conducted retrospective review of medical records for 3,140 algorithm-identified events (1,399 AMI and 1,741 stroke events) across 24 hospitals throughout Korea. The overall PPVs for the first and recurrent AMI events were around 92% and 78%, respectively, while those for the first and recurrent stroke events were around 88% and 81%, respectively. CONCLUSIONS: We successfully developed algorithms for identifying AMI and stroke events. The algorithms demonstrated high accuracy, with PPVs of approximately 90% for first events and 80% for recurrent events. These findings indicate that our algorithms hold promise as an instrumental tool for the consistent and reliable production of national CVD statistics in Korea.

Coagulation Factor Expression and Composition of Arterial Thrombi in Cancer-Associated Stroke.

BACKGROUND: Cancer is associated with an increased risk of stroke. Tumor cells activate platelets, induce a coagulation cascade, and generate thrombin. The composition of thrombi may reflect the mechanism of thrombosis, aiding the determination of the treatment strategy. Here, we investigated the composition and expression of coagulation factors in the thrombi of patients with cancer-associated stroke. METHODS: Patients with stroke who underwent endovascular thrombectomy between September 2014 and June 2020 and whose cerebral thrombi were obtained were divided into those with cancer-associated stroke (cancer group) and propensity score-matched patients without cancer (control group), using 1:1 matching based on age and sex. Immunohistochemistry was performed of the thrombi, and the composition and expression of coagulation factors were compared between groups. RESULTS: Among the 320 patients who underwent endovascular thrombectomy and who had thrombi obtained, this study included 23 patients with cancer and 23 matched controls. In both groups, the median age was 65 years, and 12 patients (52.2%) were men. Platelet composition was significantly higher in the cancer group than in the control group (median [interquartile range], 51.3% [28.0%-61.4%] versus 9.5% [4.8%-14.0%]; P<0.001). Among coagulation factors, thrombin (26.2% [16.2%-52.7%] versus 4.5% [1.3%-7.2%]; P<0.001) and tissue factors (0.60% [0.34%-2.06%] versus 0.37% [0.22%-0.60%]; P=0.024) were higher and factor X was lower (1.25% [0.39%-3.60%] versus 2.33% [1.67%-4.48%]; P=0.034) in the cancer group. There was a positive correlation between thrombin and platelets in the cancer group (r=0.666; P=0.001) but not in the control group (r=-0.167; P=0.627). CONCLUSIONS: Cerebral thrombi in patients with cancer-associated stroke showed higher proportions of platelets, thrombin, and tissue factors, suggesting their key roles in arterial thrombosis in cancer and providing a therapeutic perspective for preventing stroke in patients with cancer-associated stroke.

Cancer Prediction With Machine Learning of Thrombi From Thrombectomy in Stroke: Multicenter Development and Validation.

BACKGROUND: We aimed to develop and validate machine learning models to diagnose patients with ischemic stroke with cancer through the analysis of histopathologic images of thrombi obtained during endovascular thrombectomy. METHODS: This was a retrospective study using a prospective multicenter registry which enrolled consecutive patients with acute ischemic stroke from South Korea who underwent endovascular thrombectomy. This study included patients admitted between July 1, 2017 and December 31, 2021 from 6 academic university hospitals. Whole-slide scanning was performed for immunohistochemically stained thrombi. Machine learning models were developed using transfer learning with image slices as input to classify patients into 2 groups: cancer group or other determined cause group. The models were developed and internally validated using thrombi from patients of the primary center, and external validation was conducted in 5 centers. The model was also applied to patients with hidden cancer who were diagnosed with cancer within 1 month of their index stroke. RESULTS: The study included 70 561 images from 182 patients in both internal and external datasets (119 patients in internal and 63 in external). Machine learning models were developed for each immunohistochemical staining using antibodies against platelets, fibrin, and erythrocytes. The platelet model demonstrated consistently high accuracy in classifying patients with cancer, with area under the receiver operating characteristic curve of 0.986 (95% CI, 0.983-0.989) during training, 0.954 (95% CI, 0.937-0.972) during internal validation, and 0.949 (95% CI, 0.891-1.000) during external validation. When applied to patients with occult cancer, the model accurately predicted the presence of cancer with high probabilities ranging from 88.5% to 99.2%. CONCLUSIONS: Machine learning models may be used for prediction of cancer as the underlying cause or detection of occult cancer, using platelet-stained immunohistochemical slide images of thrombi obtained during endovascular thrombectomy.

Preprocedural determination of an occlusion pathomechanism in endovascular treatment of acute stroke: a machine learning-based decision.

OBJECTIVE: To evaluate whether an occlusion pathomechanism can be accurately determined by common preprocedural findings through a machine learning-based prediction model (ML-PM). METHODS: A total of 476 patients with acute stroke who underwent endovascular treatment were retrospectively included to derive an ML-PM. For external validation, 152 patients from another tertiary stroke center were additionally included. An ML algorithm was trained to classify an occlusion pathomechanism into embolic or intracranial atherosclerosis. Various common preprocedural findings were entered into the model. Model performance was evaluated based on accuracy and area under the receiver operating characteristic curve (AUC). For practical utility, a decision flowchart was devised from an ML-PM with a few key preprocedural findings. Accuracy of the decision flowchart was validated internally and externally. RESULTS: An ML-PM could determine an occlusion pathomechanism with an accuracy of 96.9% (AUC=0.95). In the model, CT angiography-determined occlusion type, atrial fibrillation, hyperdense artery sign, and occlusion location were top-ranked contributors. With these four findings only, an ML-PM had an accuracy of 93.8% (AUC=0.92). With a decision flowchart, an occlusion pathomechanism could be determined with an accuracy of 91.2% for the study cohort and 94.7% for the external validation cohort. The decision flowchart was more accurate than single preprocedural findings for determining an occlusion pathomechanism. CONCLUSIONS: An ML-PM could accurately determine an occlusion pathomechanism with common preprocedural findings. A decision flowchart consisting of the four most influential findings was clinically applicable and superior to single common preprocedural findings for determining an occlusion pathomechanism.

Neutrophil Recruitment in Arterial Thrombus and Characteristics of Stroke Patients with Neutrophil-Rich Thrombus.

PURPOSE: Neutrophils contribute to thrombosis. However, there is limited information on the temporal course of neutrophil recruitment in thrombosis, the contribution of neutrophils to thrombus growth, and the characteristics of stroke patients with neutrophil-rich thrombi. MATERIALS AND METHODS: After inducing carotid artery thrombosis in Institute of Cancer Research mice using ferric chloride, aged thrombi were produced by ligating the distal portion of the carotid artery in mice for 0.5, 1, 2, 3, 6, or 24 h. For thrombus analysis in stroke patients, we used registry data and thrombi that were obtained during intra-arterial thrombectomy. Immunohistochemistry was performed to determine thrombus composition. RESULTS: In the thrombi of 70 mice, Ly6G positive cell counts (neutrophils) and histone H3-positive cell counts increased in a time-dependent manner (both p<0.001). Ly6G-positive cell count was strongly correlated with histone H3-positive cell counts (r=0.910, p<0.001), but not with thrombus size (p=0.320). In 75 stroke patients, atrial fibrillation and cardioembolism were more frequent in the higher neutrophil group (32/37, 86.5%) than in the lower neutrophil group (19/38, 50%) (p=0.002). The median erythrocyte fraction was higher [52.0 (interquartile range 39.9-57.8)] in the higher neutrophil group than in the lower neutrophil group [40.3 (interquartile range 23.5-53.2)]. The fraction of neutrophils was positively correlated with that of erythrocytes (R=0.35, p=0.002). CONCLUSION: Neutrophils were recruited and increased in arterial thrombosis in a time-dependent manner; however, they were not associated with the growth of formed thrombi. Neutrophil fractions in the thrombi of stroke patients appeared to be associated with atrial fibrillation and erythrocyte fraction.

Impact of Renal Function on Short-Term Outcome After Reperfusion Therapy in Patients With Ischemic Stroke.

BACKGROUND: A high and low estimated glomerular filtration rate (eGFR) could affect outcomes after reperfusion therapy for ischemic stroke. This study aimed to determine whether renal function based on eGFR affects mortality risk in patients with ischemic stroke within 6 months following reperfusion therapy. METHODS: This prospective registry-based cohort study included 2266 patients who received reperfusion therapy between January 2000 and September 2019 and were registered in the SECRET (Selection Criteria in Endovascular Thrombectomy and Thrombolytic Therapy) study or the Yonsei Stroke Cohort. A high and low eGFR were based on the Chronic Kidney Disease Epidemiology Collaboration equation and defined, respectively, as the 5th and 95th percentiles of age- and sex-specific eGFR. Occurrence of death within 6 months was compared among the groups according to their eGFR such as low, normal, or high eGFR. RESULTS: Of the 2266 patients, 2051 (90.5%) had a normal eGFR, 110 (4.9%) a low eGFR, and 105 (4.6%) a high eGFR. Patients with high eGFR were younger or less likely to have hypertension, diabetes, or atrial fibrillation than the other groups. Active cancer was more prevalent in the high-eGFR group. During the 6-month follow-up, there were 24 deaths (22.9%) in the high-eGFR group, 37 (33.6%) in the low-eGFR group, and 237 (11.6%) in the normal-eGFR group. After adjusting for variables with P<0.10 in the univariable analysis, 6-month mortality was independently associated with high eGFR (hazard ratio, 2.22 [95% CI, 1.36-3.62]; P=0.001) and low eGFR (HR, 2.29 [95% CI, 1.41-3.72]; P=0.001). These associations persisted regardless of treatment modality or various baseline characteristics. CONCLUSIONS: High eGFR as well as low eGFR were independently associated with 6-month mortality after reperfusion therapy. Kidney function could be considered a prognostic factor in patients with ischemic stroke after reperfusion therapy.

Early depression screening and short-term functional outcome in hospitalized patients for acute ischemic stroke.

Background: Patients with ischemic stroke are at high risk for post-stroke depression (PSD). There are limited data regarding the clinical impact of early PSD, assessed in hospitalized patients with acute ischemic stroke. Methods: This hospital-based observational cohort study included consecutive patients with acute ischemic stroke or transient ischemic attack between July 2019 and June 2021. In the study hospital, all admitted patients were systematically screened for depression. The depression was screened using the Patient Health Questionnaire-9 (PHQ-9), and PHQ-9 positivity indicated early PSD, which was defined as a score of >4. Logistic regression analyses were used to compare the rates of poor functional outcomes at 3 months in patients with and without PHQ-9 positivity. Results: Among 1339 patients admitted during the study period, 775 were included, with a median age of 68.0 years, and 316 (40.8%) were women. A total of 111 (14.3%) patients were PHQ-9 positive. History of cancer and early neurological deterioration were independently associated with PHQ-9 positivity. Poor functional outcomes at 3 months were observed in 147 patients (18.8%). PHQ-9 positivity independently showed a 2.2-fold increased risk of poor functional outcome at 3 months (Odds ratio 2.23; 95% confidence interval 1.05-4.73, P = 0.037). Conclusions: Patients with history of cancer and early neurological deterioration were at risk for early PSD. Early PSD was independently associated with poor functional outcomes at 3 months. The identification of early depression could offer opportunities for further questioning and exploration of symptoms, as well as interventions.

Clinical outcomes of rescue stenting for failed endovascular thrombectomy: a multicenter prospective registry.

BACKGROUND: Mechanical thrombectomy (MT) is a primary endovascular modality for acute intracranial large vessel occlusion. However, further treatment, such as rescue stenting, is occasionally necessary for refractory cases. We aimed to investigate the efficacy and safety of rescue stenting in first-line MT failure and to identify the clinical factors affecting its clinical outcome. METHODS: A multicenter prospective registry was designed for this study. We enrolled consecutive patients who underwent rescue stenting for first-line MT failure. Endovascular details and outcomes, follow-up patency of the stented artery, and clinical outcomes were summarized and compared between the favorable and unfavorable outcome groups. RESULTS: A total of 78 patients were included. Intracranial atherosclerotic stenosis was the most common etiology for rescue stenting (97.4%). Seventy-seven patients (98.7%) were successfully recanalized by rescue stenting. A favorable outcome was observed in 66.7% of patients. Symptomatic intracranial hemorrhage and mortality were observed in 5.1% and 4.0% of patients, respectively. The stented artery was patent in 82.1% of patients on follow-up angiography. In a multivariable analysis, a patent stent on follow-up angiography was an independent factor for a favorable outcome (OR 87.6; 95% CI 4.77 to 1608.9; p=0.003). Postprocedural intravenous maintenance of glycoprotein IIb/IIIa inhibitor was significantly associated with the follow-up patency of the stented artery (OR 5.72; 95% CI 1.45 to 22.6; p=0.013). CONCLUSIONS: In this multicenter prospective registry, rescue stenting for first-line MT failure was effective and safe. For a favorable outcome, follow-up patency of the stented artery was important, which was significantly associated with postprocedural maintenance of glycoprotein IIb/IIIa inhibitors.

Characterization of Ferric Chloride-Induced Arterial Thrombosis Model of Mice and the Role of Red Blood Cells in Thrombosis Acceleration.

PURPOSE: The ferric chloride (FeCl3)-induced thrombosis model is widely used for thrombosis research. However, it lacks standardization with uncertainty in the exact mechanism of thrombosis. This study aimed to characterize thrombus formation in a mouse model. MATERIALS AND METHODS: We investigated thrombus formation and stability using various FeCl3 concentrations (10%, 20%, 30%, 40%, and 50%, w/v) in carotid arteries of the Institute of Cancer Research (ICR) and C57BL/6N mice using the FeCl3-induced thrombosis model. We also investigated thrombus histopathology using immunohistochemistry and electron microscopy. RESULTS: Higher FeCl3 concentrations induced dose-dependent, faster, larger, and more stable thrombus formation in both strains of mice. However, the ICR mice showed better dose-responses in thrombus formation and stability compared to the C57BL/6N mice. Thrombi were fibrin- and platelet-rich without significant changes across FeCl3 concentrations. However, the content of red blood cells (RBCs) increased with increasing FeCl3 concentrations (p for trend <0.001) and inversely correlated with time to occlusion (r=-0.65, p<0.001). While platelets and fibrin were evenly distributed over the thrombus, RBCs were predominantly located near the FeCl3 treatment area. Transmission electron microscopy showed that RBCs attached to and were surrounded by aggregates of degranulated platelets, suggesting their potential role in platelet activation. CONCLUSION: Faster and larger thrombus formation is induced in a dose-dependent manner by a wide range of FeCl3 concentrations, but the stable thrombus formation requires higher FeCl3 concentrations. Mouse strain affects thrombus formation and stability. RBCs and their interaction with platelets play a key role in the acceleration of FeCl3-induced thrombosis.

The role of cardiac CT throughout the full cardiac cycle in diagnosing patent foramen ovale in patients with acute stroke.

OBJECTIVES: We explored the hypothesis that the diagnostic performance of cardiac computed tomography (CT) throughout the full cardiac cycle would be superior to single-phase CT and comparable to transesophageal echocardiography (TEE) in diagnosing patent foramen ovale (PFO). METHODS AND RESULTS: From May 2011 to April 2015, 978 patients with stroke were diagnosed with PFO by TEE. In patients with stroke, cardiac CT was performed if the patients had more than two cardiovascular risk factors. We prospectively enrolled 70 patients with an indication for cardiac CT. Cardiac CT images were reconstructed at 10% increments of the R-R interval. The sensitivity of cardiac CT throughout the full cardiac cycle in diagnosing PFO was compared to that for TEE and single-phase cardiac CT. To evaluate the specificity of cardiac CT, we analyzed patients without PFO confirmed by TEE who underwent cardiac CT within 1 month of pre-cardiac surgery. Sixty-six patients with cardiac CT and TEE were included in the final analysis. Throughout the full cardiac cycle, cardiac CT had a sensitivity of 89.4% and a specificity of 92.3% in diagnosing PFO, compared to TEE as a reference. PFO was primarily detected in the 60% and 70% intervals in 10-phase reconstructed images. The sensitivity of PFO diagnosis with cardiac CT was 81.8% when analyzing both the 60% and 70% intervals instead of the full cardiac cycle. CONCLUSION: Cardiac CT throughout the full cardiac cycle outperforms single-phase cardiac CT in detecting PFO. Cardiac CT can be used as an alternative method to TEE for detecting PFO in stroke patients. KEY POINTS: • Throughout the full cardiac cycle, cardiac computed tomography (CT) had a sensitivity of 89.4% and a specificity of 92.3% in diagnosing patent foramen ovale (PFO), compared to transesophageal echocardiography. • The sensitivity of diagnosing patent foramen ovale with cardiac CT was 81.8% when analyzing 60% and 70% R-R intervals instead of the full cardiac cycle. • Cardiac CT with retrospective electrocardiographic gating throughout the full cardiac cycle can increase the detectability of PFO, compared to single-phase cardiac CT.

NSrp70 is a lymphocyte-essential splicing factor that controls thymocyte development.

Alternative pre-mRNA splicing is a critical step to generate multiple transcripts, thereby dramatically enlarging the proteomic diversity. Thus, a common feature of most alternative splicing factor knockout models is lethality. However, little is known about lineage-specific alternative splicing regulators in a physiological setting. Here, we report that NSrp70 is selectively expressed in developing thymocytes, highest at the double-positive (DP) stage. Global splicing and transcriptional profiling revealed that NSrp70 regulates the cell cycle and survival of thymocytes by controlling the alternative processing of various RNA splicing factors, including the oncogenic splicing factor SRSF1. A conditional-knockout of Nsrp1 (NSrp70-cKO) using CD4Cre developed severe defects in T cell maturation to single-positive thymocytes, due to insufficient T cell receptor (TCR) signaling and uncontrolled cell growth and death. Mice displayed severe peripheral lymphopenia and could not optimally control tumor growth. This study establishes a model to address the function of lymphoid-lineage-specific alternative splicing factor NSrp70 in a thymic T cell developmental pathway.

Modeling Sialidosis with Neural Precursor Cells Derived from Patient-Derived Induced Pluripotent Stem Cells.

Sialidosis, caused by a genetic deficiency of the lysosomal sialidase gene (NEU1), is a systemic disease involving various tissues and organs, including the nervous system. Understanding the neurological dysfunction and pathology associated with sialidosis remains a challenge, partially due to the lack of a human model system. In this study, we have generated two types of induced pluripotent stem cells (iPSCs) with sialidosis-specific NEU1G227R and NEU1V275A/R347Q mutations (sialidosis-iPSCs), and further differentiated them into neural precursor cells (iNPCs). Characterization of NEU1G227R- and NEU1V275A/R347Q- mutated iNPCs derived from sialidosis-iPSCs (sialidosis-iNPCs) validated that sialidosis-iNPCs faithfully recapitulate key disease-specific phenotypes, including reduced NEU1 activity and impaired lysosomal and autophagic function. In particular, these cells showed defective differentiation into oligodendrocytes and astrocytes, while their neuronal differentiation was not notably affected. Importantly, we found that the phenotypic defects of sialidosis-iNPCs, such as impaired differentiation capacity, could be effectively rescued by the induction of autophagy with rapamycin. Our results demonstrate the first use of a sialidosis-iNPC model with NEU1G227R- and NEU1V275A/R347Q- mutation(s) to study the neurological defects of sialidosis, particularly those related to a defective autophagy-lysosome pathway, and may help accelerate the development of new drugs and therapeutics to combat sialidosis and other LSDs.

Immediate and Long-Term Outcomes of Reperfusion Therapy in Patients With Cancer.

Background and Purpose: Patients with acute stroke are often accompanied by comorbidities, such as active cancer. However, adequate treatment guidelines are not available for these patients. The purpose of this study was to evaluate the association between cancer and the outcomes of reperfusion therapy in patients with stroke. Methods: We compared treatment outcomes in patients who underwent reperfusion therapy, using a nationwide reperfusion therapy registry. We divided the patients into 3 groups according to cancer activity: active cancer, nonactive cancer, and without a history of cancer. We investigated reperfusion processes, 24-hour neurological improvement, adverse events, 3-month functional outcome, and 6-month survival and related factors after reperfusion therapy. Results: Among 1338 patients who underwent reperfusion therapy, 62 patients (4.6%) had active cancer, 78 patients (5.8%) had nonactive cancer, and 1198 patients (89.5%) had no history of cancer. Of the enrolled patients, 969 patients received intravenous thrombolysis and 685 patients underwent endovascular treatment (316 patients received combined therapy). Patients with active cancer had more comorbidities and experienced more severe strokes; however, they showed similar 24-hour neurological improvement and adverse events, including cerebral hemorrhage, compared with the other groups. Although the functional outcome at 3 months was poorer than the other groups, 36.4% of patients with active cancer showed functional independence. Additionally, 52.9% of the patients with determined stroke etiology showed functional independence despite active cancer. During the 6-month follow-up, 46.6% of patients with active cancer died, and active cancer was independently associated with poor survival (hazard ratio, 3.973 [95% CI, 2.528­6.245]). Conclusions: In patients with active cancer, reperfusion therapy showed similar adverse events and short-term outcomes to that of other groups. While long-term prognosis was worse in the active cancer group than the nonactive cancer groups, not negligible number of patients had good functional outcomes, especially those with determined stroke mechanisms.

Prognostic effect of increased left ventricular wall thickness in severe aortic stenosis.

BACKGROUND: It is unclear whether increased left ventricular (LV) thickness is associated with worse clinical outcomes in severe aortic stenosis (AS). The aim of this study was to determine the effect of increased LV wall thickness (LVWT) on major clinical outcomes in patients with severe AS. METHODS AND RESULTS: This study included 290 severe AS patients (mean age 69.4 ± 11.0 years; 136 females) between January 2008 and December 2018. For outcome assessment, the endpoint was defined as death from all causes, cardiovascular death, and the aortic valve replacement (AVR) surgery rate. During follow-up (48.7 ± 39.0 months), 157 patients had AVR, 43 patients died, and 28 patients died from cardiovascular causes. Patients with increased LVWT underwent AVR surgery much more than those without LVWT (60.0% vs. 39.0%, p < 0.001). Furthermore, in patients with increased LVWT, the all-cause and cardiovascular death rates were significantly lower in the AVR group than in the non-AVR group (8.8% vs. 27.3%, p < 0.001, 4.8%, vs. 21.0%, p < 0.001). Multivariate analysis revealed that increased LVWT, age, dyspnea, and AVR surgery were significantly correlated with cardiovascular death. CONCLUSIONS: In patients with severe AS, increased LVWT was associated with a higher AVR surgery rate and an increased rate of cardiovascular death independent of other well-known prognostic variates. Thus, these findings suggest that increased LVWT might be used as a potential prognostic factor in severe AS patients.

Association between the severity of liver fibrosis and cardiovascular outcomes in patients with type 2 diabetes.

BACKGROUND AND AIM: Cardiovascular disease (CVD) is the principal cause of death in patients with type 2 diabetes (T2D). In this study, we assessed whether liver fibrosis predicted the risk of CVD in patients with T2D. METHODS: A total of 1481 patients who had commenced oral antidiabetic drugs to treat newly diagnosed T2D between 2006 and 2010 were recruited. The fibrosis-4 index (FIB-4), non-alcoholic fatty liver disease fibrosis score (NFS), and BARD score were used to assess fibrotic burden at the time of T2D diagnosis. RESULTS: During the follow-up period (median 88.1 [interquartile range 36.6-113.6] months), 242 (16.3%) patients developed CVD. CVD occurred frequently in older patients and was associated with hypertension; metabolic syndrome; obesity; smoking; administration of statin, which is an antihyperlipidemic drug; lower platelet counts; lower alanine aminotransferase, total cholesterol, and HbA1c levels; higher C-peptide and homeostatic model assessment of insulin resistance levels; and higher FIB-4, NFS, and BARD score (all P < 0.05). FIB-4 (hazard ratio [HR] = 1.163), NFS (HR = 1.322), BARD score (HR = 1.564), metabolic syndrome (HR = 1.556), smoking (HR = 2.829), and statin use (HR = 0.603) independently predicted the risk of CVD (all P < 0.05). The cumulative incidence of CVD was significantly different among groups stratified by liver fibrotic burden (all P < 0.05, log-rank test). Competing risk analysis showed a significant association between the severity of liver fibrosis and CVD development (all P < 0.001, Gray's test). CONCLUSIONS: The severity of liver fibrosis independently predicted CVD in patients with T2D. Thus, assessment of liver fibrosis might allow physicians to optimize the timing of appropriate cardiovascular interventions in such patients.

Association between flat-panel computed tomography hyperattenuation and clinical outcome after successful recanalization by endovascular treatment.

OBJECTIVE: Hyperattenuation on CT scanning performed immediately after endovascular treatment (EVT) is known to be associated with the final infarct. As flat-panel CT (FPCT) scanning is readily accessible within their angiography suite, the authors evaluated the ability of the extent of hyperattenuation on FPCT to predict clinical outcomes after EVT. METHODS: Patients with successful recanalization (modified Thrombolysis in Cerebral Infarction grade 2b or 3) were reviewed retrospectively. The extent of hyperattenuation was assessed by the Alberta Stroke Program Early CT Score on FPCT (FPCT-ASPECTS). FPCT-ASPECTS findings were compared according to functional outcome and malignant infarction. The predictive power of the FPCT-ASPECTS with initial CT images before EVT (CT-ASPECTS) and follow-up diffusion-weighted images (MR-ASPECTS) was also compared. RESULTS: A total of 235 patients were included. All patients were treated with mechanical thrombectomy, and 45.5% of the patients received intravenous tissue plasminogen activator. The mean (± SD) time from stroke onset to recanalization was 383 ± 290 minutes. The FPCT-ASPECTS was significantly different between patients with a favorable outcome and those without (mean 9.3 ± 0.9 vs 6.7 ± 2.6) and between patients with malignant infarction and those without (3.4 ± 2.9 vs 8.8 ± 1.4). The FPCT-ASPECTS was an independent factor for a favorable outcome (adjusted OR 3.28, 95% CI 2.12-5.01) and malignant infarction (adjusted OR 0.42, 95% CI 0.31-0.57). The area under the curve (AUC) of the FPCT-ASPECTS for a favorable outcome (0.862, cutoff ≥ 8) was significantly greater than that of the CT-ASPECTS (0.637) (p < 0.001) and comparable to that of the MR-ASPECTS (0.853) (p = 0.983). For malignant infarction, the FPCT-ASPECTS was also more predictive than the CT-ASPECTS (AUC 0.906 vs 0.552; p = 0.001) with a cutoff of ≤ 5. CONCLUSIONS: The FPCT-ASPECTS was highly predictive of clinical outcomes in patients with successful recanalization. FPCT could be a practical method to immediately predict clinical outcomes and thereby aid in acute management after EVT.

Outcome of Stroke Patients with Cancer and Nonbacterial Thrombotic Endocarditis.

BACKGROUND AND PURPOSE: Nonbacterial thrombotic endocarditis (NBTE) is a cause of stroke in cancer. However, clinical characteristics and outcomes in stroke patients with cancer-associated NBTE are not well known. METHODS: We included consecutive patients with stroke and active cancer over a 9-year period who underwent echocardiography. We retrospectively compared clinical characteristics and presence of metastasis between patients with NBTE, those with cryptogenic etiologies, and those with determined etiologies. We also investigated mortality and stroke events during the 6-month follow-up. RESULTS: Among the 245 patients, 20 had NBTE, 96 had cryptogenic etiologies, and 129 had determined etiologies. Metastasis was seen in all 20 patients (100%) with NBTE, 69.8% in patients with cryptogenic etiology, and 48.8% in patients with or determined etiology. During the 6-month follow-up, 127 patients (51.8%) developed stroke and/or died (death in 110 [44.9%] and stroke events in 55 [22.4%]). Patients with NBTE showed significantly higher mortality (80%) and stroke occurrence (50%) than those with cryptogenic etiologies (mortality 54.2%, stroke 25.0%, log-rank P=0.006) and determined etiologies (mortality 32.6%, stroke 16.3%, log-rank P<0.001). In a multivariate Cox proportional hazard analysis, the presence of NBTE was independently associated with composite outcomes of mortality and stroke events (hazard ratio, 1.941; 95% confidence interval, 1.052 to 3.690). CONCLUSIONS: NBTE should be suspected as a potential cause of stroke in patients with metastatic cancer. Patients with NBTE have a high risk of recurrent stroke and mortality. Future studies are necessary to determine strategies to reduce stroke recurrence in patients with NBTE.