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At least 19 recordsLinked to original sources
PubMed2026

Nonbacterial Thrombotic Endocarditis Unmasking Concomitant Monoclonal Gammopathy of Undetermined Significance (MGUS) by Manifesting as Stroke.

Nonbacterial thrombotic endocarditis (NBTE) is a rare condition characterized by sterile platelet-fibrin vegetations on cardiac valves in the absence of systemic infection. The pathogenesis of marantic endocarditis is driven by endothelial dysfunction and a systemic hypercoagulable state. In contrast to infective endocarditis, vegetations in NBTE lack significant inflammatory infiltrates and do not yield positive blood cultures. NBTE typically comes to clinical attention via systemic embolic events, with cerebrovascular accidents serving as a clinical hallmark and constituting over 50% of cases. While NBTE is commonly associated with mucin-producing adenocarcinomas of the lung, pancreas, and gastrointestinal tract, its occurrence secondary to hematological malignancies or precursor plasma cell dyscrasias like monoclonal gammopathy of undetermined significance (MGUS) is exceedingly rare, particularly in young individuals. We report the case of a previously healthy 35-year-old woman who presented with acute-onset blurred vision. Neuroimaging via magnetic resonance imaging (MRI) revealed an acute left occipital infarct along with multiple chronic infarcts, raising a strong suspicion of a recurrent embolic process. A transesophageal echocardiogram (TEE) demonstrated two vegetations on the aortic valve with moderate transvalvular regurgitation; in the context of persistent negative blood cultures, these findings supported the diagnosis of NBTE. The patient was managed with systemic anticoagulation. A comprehensive hypercoagulable and autoimmune workup revealed an elevated lambda free light chain level with a decreased kappa/lambda ratio. Subsequent bone marrow biopsy and cytogenetic analysis established a diagnosis of MGUS featuring high-risk genomic aberrations, specifically an immunoglobulin heavy chain/musculoaponeurotic fibrosarcoma (IGH/MAF) rearrangement and the loss of chromosome 13 in a polyploid (3n, 4n) background, findings consistent with plasma cell neoplasia. The prevalence of MGUS in individuals under the age of 40 is exceptionally low, estimated at less than 0.3%. This case underscores NBTE as a critical finding that can unmask underlying, atypical plasma cell neoplasms. It highlights the necessity of an exhaustive diagnostic evaluation for occult hematological disorders and high-risk cytogenetic features in young patients presenting with multi-territory embolic strokes.

igh/maf rearrangement↗
PubMed2026

Ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated non-small-cell lung cancer after disease progression on EGFR tyrosine kinase inhibitor therapy (HARMONi): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: Ivonescimab has shown clinical efficacy in non-small-cell lung cancer (NSCLC). We aimed to assess the efficacy and safety of ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated NSCLC whose disease progressed after third-generation EGFR tyrosine kinase inhibitor (TKI) therapy. METHODS: HARMONi is a randomised, placebo-controlled, double-blind, phase 3 trial done at 114 cancer centres and hospitals across Asia, Europe, and North America. Eligible patients were aged at least 18 years (upper limit: 75 years in Asia) with stage IIIB/IIIC or IV non-squamous EGFR-mutated NSCLC, disease progression after treatment with a third-generation EGFR-TKI, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) via a centralised interactive voice response system or interactive web response system to receive ivonescimab (20 mg/kg) or placebo plus pemetrexed (500 mg/m2) and carboplatin (target area under the curve 5 mg/mL per min) intravenously every 3 weeks. Randomisation was stratified by brain metastases status at enrolment and geographical region. The primary endpoints were progression-free survival by blinded independent radiology review committee and overall survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov (NCT06396065), has completed enrolment, and is ongoing for treatment and follow-up. FINDINGS: From Jan 25, 2022, to Oct 1, 2024, 660 individuals were screened for eligibility; of these, 438 were enrolled and randomly assigned to receive ivonescimab plus chemotherapy or placebo plus chemotherapy (219 per group). Of enrolled patients, 257 (59%) were female and 181 (41%) were male; 306 (70%) reported race as Asian, and 105 (24%) as White. At a median follow-up of 22&#xb7;3 months (95% CI 21&#xb7;5-23&#xb7;0), 275 progression or death events had occurred in 345 patients (129 events among 172 patients in the ivonescimab plus chemotherapy group and 146 events among 173 patients in the placebo plus chemotherapy group). Median progression-free survival was 6&#xb7;8 months (95% CI 5&#xb7;7-7&#xb7;1) in the ivonescimab plus chemotherapy group versus 4&#xb7;4 months (4&#xb7;1-5&#xb7;5) in the placebo plus chemotherapy group (hazard ratio [HR] 0&#xb7;52; 95% CI 0&#xb7;41-0&#xb7;66; p<0&#xb7;0001). At a median follow-up of 29&#xb7;7 months (95% CI 27&#xb7;7-31&#xb7;0), 262 deaths occurred in 438 patients (122 in the ivonescimab plus chemotherapy group and 140 in the placebo plus chemotherapy group). Median overall survival was 16&#xb7;8 months (14&#xb7;3-19&#xb7;0) in the ivonescimab plus chemotherapy group versus 14&#xb7;0 months (12&#xb7;8-15&#xb7;7) in the placebo plus chemotherapy group (HR 0&#xb7;79; 0&#xb7;62-1&#xb7;01). The most common grade 3-4 treatment-related adverse events in the ivonescimab plus chemotherapy versus the placebo plus chemotherapy group were decreased neutrophil count (42 [19%] of 218 vs 36 [17%] of 218), decreased white blood cell count (28 [13%] vs 24 [11%]), decreased platelet count (27 [12%] vs 14 [6%]), and anaemia (22 [10%] vs 27 [12%]). Serious treatment-related adverse events occurred in 61 (28%) patients in the ivonescimab plus chemotherapy group and 33 (15%) patients in the placebo plus chemotherapy group. Treatment-related adverse events led to death in four patients (disease progression, multiple organ dysfunction syndrome, and hepatic failure, each in one patient; gastrointestinal haemorrhage and pulmonary embolism in one patient) in the ivonescimab plus chemotherapy group and five patients (pneumonitis, myocardial infarction, cerebrovascular accident, cognitive disorder, and embolic stroke, each in one patient) in the placebo plus chemotherapy group. INTERPRETATION: Ivonescimab plus chemotherapy showed a clinically meaningful and statistically significant progression-free survival benefit in patients with EGFR-mutated NSCLC after progression on EGFR-TKI therapy. The clinical benefit and lack of new safety signals of ivonescimab with chemotherapy support the potential for the combination as a new treatment option in this patient population. FUNDING: Summit Therapeutics.

Humans↗
PubMed1977

Isolated aortic valve replacement in patients older than 65 years.

The results of 196 isolated aortic valve replacements in patients older than 65 years were analyzed. Eighty-four percent of patients were in New York Heart Association (NYHA) functional class III or IV preoperatively. The operative mortality was 12% for all cases and 9% for elective cases. Actuarial probability of five-year survival was 55% for the entire group and 61% for discharged patients. Myocardial failure and congestive heart failure were the most common causes of early and late postoperative death, respectively. Embolic strokes occurred in 16% of discharged patients and caused substantial disability in 9%. At the termination of the study, 94% of surviving patients were in NYHA class I or II, and none were in class IV. Aortic valve replacement in elderly patients entails reasonable operative risk, and results in satisfactory postoperative rehabilitation.

Age Factors↗
PubMed2025

Identification of Differential Proteins in Thrombi of Cardioembolic and Atherothrombotic Etiology in Patients with Ischemic Stroke.

Knowing the precise etiology in ischemic stroke is necessary to ensure accurate diagnosis and decide on appropriate preventive treatments, especially in those of undetermined cause. Analysis of the thrombus protein composition could be useful to identify diagnostic biomarkers to help determine the stroke origin. Thrombi from 54 ischemic stroke patients with large vessel occlusion (LVO), of cardioembolic and atherothrombotic etiology, were analyzed using a proteomics approach. The proteome profile was compared between them to detect differential proteins of each etiology. Peptides of those differential proteins were quantified and related to the neurological function and clinical status of the patients. Of the 516 proteins identified, three showed significant differences between atherothrombotic and cardioembolic thrombi. These were fibronectin (FINC), 2,3-bisphosphoglycerate mutase (PMGE), and tropomyosin-1 (TPM1). Combining these proteins in a biomarker panel provided good sensitivity and high specificity for differentiating cardioembolic and atherothrombotic strokes. In addition, several of the quantified peptide levels correlated with clinical parameters related to stroke severity and prognosis. Three proteins differentially detected in ischemic stroke thrombi could be useful tools for accurately diagnosing ischemic stroke etiology, particularly in cases of undetermined cause. These biomarkers should be further analyzed in prospective multicenter studies to demonstrate their usefulness.

Humans↗
PubMed2025

Genetic Downregulation of Interleukin-6 Signaling, Coagulation Function, and Risk of Thromboembolic Disease.

BACKGROUND: Although genetic evidence supports IL-6 (interleukin-6) signaling inhibition as protective against atherosclerotic disease, its potential effects on thromboembolic outcomes are not well established. We conducted a Mendelian randomization analysis to investigate the association of genetically proxied IL-6 signaling inhibition with venous thromboembolism, cardioembolic stroke, and coagulation cascade protein levels. METHODS: IL-6 signaling inhibition was proxied using the rs2228145 IL6R missense variant, which impairs classical IL-6 signaling and lowers CRP (C-reactive protein) levels. Genetic associations with thromboembolic disease outcomes were obtained from genome-wide association studies of venous thromboembolism (81&#x2009;190 cases) and cardioembolic stroke (10&#x2009;804 cases). As atherosclerotic comparator traits, we included coronary artery disease (181&#x2009;522 cases) and large-artery atherosclerotic stroke (6399 cases). Genetic associations with 35 coagulation cascade protein levels were obtained from the UK Biobank (n=6218) and deCODE cohorts (n=35&#x2009;559). Mendelian randomization estimates were derived using the Wald ratio method, scaled per 1-unit decrease in natural log-transformed CRP levels. RESULTS: Genetically proxied IL-6 signaling inhibition was associated with increased risk of venous thromboembolism (odds ratio [OR], 1.31 [95% CI, 1.16-1.47], P=6.5&#xd7;10-6) but not with cardioembolic stroke (OR, 1.25 [95% CI, 0.73-2.14], P=0.42). Conversely, protective associations were observed for both coronary artery disease and large-artery atherosclerotic stroke. Proteomic analyses demonstrated significant reductions in levels of 5 procoagulant and 7 anticoagulant or antifibrinolytic proteins. CONCLUSIONS: These findings suggest that IL-6 signaling inhibition dysregulates coagulation homeostasis and increases venous thromboembolism risk. Further experimental, translational, and epidemiologic studies are warranted to delineate underlying mechanisms and to evaluate thromboembolic safety in pharmacologic IL-6 signaling inhibition.

Humans↗
PubMed2026

Prophylactic Surgical Left Atrial Appendage Closure in Bioprosthetic Aortic Valve Replacement: Short-Term Outcomes of Randomized Controlled LAA-CLOSURE Trial.

BACKGROUND: Surgical closure of the left atrial appendage (LAA) reduces stroke risk in patients with atrial fibrillation (AF) undergoing cardiac surgery. We evaluated the safety and efficacy of prophylactic LAA closure during bioprosthetic surgical aortic valve replacement in patients without prior AF. METHODS: In this investigator-initiated, academic, randomized, open-label, multicenter LAA-CLOSURE (Left Atrial Appendage CLOSURE for the Prevention of Thromboembolisms in Patients Undergoing Aortic Bioprosthesis Surgery) trial, 921 patients without prior AF undergoing bioprosthetic surgical aortic valve replacement with or without concomitant surgery were randomized and 904 patients included in the modified intention-to-treat analysis (prophylactic LAA closure, n=445; or usual care, n=459). Median age was 73&#x2009;years (interquartile range, 69-76), 34.8% were women, and 49% had concomitant coronary artery disease. The primary end point was a composite of cardiovascular death, stroke, or systemic embolism at 30&#x2009;days. RESULTS: The primary end point occurred in 10 of 434 (2.2%) patients in the LAA closure group and 14 of 452 (3.1%) patients in the control group; however, the treatment effect changed direction at &#x2248;7&#x2009;days. In the time-split Cox regression model, hazard ratios were 2.4 (95% CI, 0.62-9.4; P=0.20) between 0 and 7&#x2009;days and 0.29 (95% CI, 0.080-1.0; P=0.056) between 7 and 30&#x2009;days. No closure-related serious complications or differences in bleeding were observed. Postoperative AF occurred in 205 of 445 (46.1%) versus 184 of 459 (40.1%) patients (relative risk, 1.1 [95% CI, 0.99-1.3]; P=0.07), and AF at discharge in 40 of 445 (9.2%) versus 34 of 459 (7.7%) patients (relative risk, 1.2 [95% CI, 0.77-1.8]; P=0.44), in the closure and control groups, respectively. CONCLUSIONS: Prophylactic LAA closure during bioprosthetic surgical aortic valve replacement was safe and did not increase bleeding. REGISTRATION: URL: clinicaltrials.gov; Unique Identifier: NCT02321137.

Aged↗
PubMed1976

Laboratory note. EEG changes after acute cerebral embolism.

Embolism of the right middle cerebral artery regularly failed to induce clinical or electrical seizure activity during acute ischemia in primates. This negative correlation casts some doubt on the popular interpretation of seizures at the outset of clinical stroke as evidence of cerebral embolism.

Animals↗
PubMed1979

Surgery of the aortic arch branches and vertebral arteries.

Experience with 192 operations of vascular reconstruction for atherosclerosis in the proximal brachiocephalic and vertebral arteries is reported. These procedures constitute only 10 per cent of operations for extracranial arterial occlusive cerebrovascular disease at the University of California, San Francisco, in the past 20 years. All patients were asymptomatic. Except for six patients with cerebral embolization from ulcerating lesions, symptoms resulted from cerebral hypoperfusion. Prevention of ultimate stroke was the primary objective of operation in patients with embolization and in patients with stenosis or occlusion of the common carotid arteries. Purely obstructive lesions in the subclavian and vertebral arteries were symptomatic only when there was bilateral involvement and the objective of operation was the relief of disabling symptoms of hypoperfusion for these otherwise essentially benign lesions. Prior correction of associated stenosis of the carotid artery often removed the need for a proximal operation. The majority of the operations were endarterectomy or transposition, or combinations of the two. Cervical bypass grafts, because of their less certain durability, were used only when a more direct operation was neither feasible nor safe.

Aorta, Thoracic↗
PubMedDate not supplied

Blood coagulation and plasma fibrinolytic enzyme system pathophysiology in stroke.

Plasma fibrinogen chromatography is a method for quantification of high molecular weight fibrinogen complexes (HMWFC), native fibrinogen and other fibrinogen derivatives in plasma. Enchanced formation of fibrin, intravascular coagulation, thrombus formation, etc., are reflected by elevation of plasma HMWFC, and the method distinguishes between subjects with normal and pathological rates of fibrin formation. Serial standard blood coagulation assays, including plasma fibrinogen chromatography, and neurological studies were performed on 220 patients admitted to a stroke unit. Findings from patients with cerebral infarction were compared against those of three control groups: (1)normals, (2)a stroke control group and(3)a stroke risk factor group. Plasma HMWFC findings were significantly (p less than 0.001) higher in the stroke risk factor group than in the normals. Plasma HMWFC values were significantly higher (p less than 0.001) in the cerebral infarction patients than in any of the control groups, and plasma fibrinogen, plasminogen, alpha1-antitrypsin and alpha2-macroglobulin also were significiantly higher (p less than 0.001) in the patients. The greater the degree of initial neurological deficit, the greater were plasma HMWFC values (p less than 0.001), and high HMWFC values were associated with poor clinical outcome. Plasma HMWFC values were significantly higher (p less than 0.001) in patients with intracerebral hemorrhage, subarachnoid hemorrhage and cerebral embolism. These findings docunment the fact that a high proportion of stroke patients have coagulopathy, characterized by pathological enhancement of fibrin formation.

Antithrombins↗
PubMedDate not supplied

Experimental regional cerebral ischemia in the middle cerebral artery territory in primates. Part 2: Effects on brain water and electrolytes in the early phase of MCA stroke.

Acute regional cerebral ischemia was produced in the middle cerebral artery (MCA) territory in monkeys (Macaca mulatta) by selective embolization of the internal carotid (ICA) bifurcation with minimum surgical intervention in the neck under sedated conditions. Two of five hours after embolization, brain water (measurement of dry weight) and tissue concentration of sodium and potassium were determined in the tissues of the sylvian cortex, putamen and subcortical white matter in the affected MCA territory. As early as three hours, initial increase in brain water was detected in the samples of the putament without noticeable change in tissue electrolytes in two of three animals. Gross ischemic swelling of the gray matter, in both the sylvian cortex and putamen, became obvious in six of eight animals after four to five hours. This swollen gray matter showed marked increase in brain water (up to 36% swelling), increase in tissue sodium (up to 100% of the control value), and decrease in tissue potassium (down to 55%). On the other hand, edema in the white matter, if present at all, was minimal without detectable change in tissue electrolytes and was always accompanied by much greater ( greater than two to seven times) edema in the gray matter. Thus, the gray matter edema, in both the deep subcortical structures and the cortex, appeared to play the major role in the development of hemispheric swelling of the brain which may begin within hours of the onset of the MCA stroke in monkeys. Microscopically, the swollen gray matter which showed more than 10% swelling with a definite shift of tissue sodium and potassium content appeared to be dead tissue. However, early edema in the gray matter which showed less than 10% swelling without detectable change in electrolytes might be caused by simple diffusion of water through the dysfunctional capillary wall or cell membrane with or without a permeability gradient between the intravascular cerebrospinal fluid and cerebral tissue compartment and might possibly be reversible.

Animals↗
PubMed1979

Cardiac embolic cerebrovascular disease.

Cerebral emoli may originate in the heart, the carotid arterial system, or the aortic arch. If the source of the embolus can be located, medical or surgical therapy may be able to prevent the occurrence of further strokes.

Aged↗
PubMed1979

Antiplatelet drugs in thromboembolism.

Evidence is mounting that three drugs that inhibit platelet function--aspirin, dipyridamole, and sulfinpyrazine--have an antithrombotic effect in humans. Particularly in men, aspirin is beneficial in controlling transient ischemic attacks and stroke, and there is evidence that it may be effective in preventing thrombotic and embolic complication of hip surgery. It abolishes symptoms in peripheral ischemia associated with thrombocytosis and spontaneous platelet aggregation and may prove effective in coronary artery disease. When combined with oral anticoagulants, aspirin is more effective than oral anticoagulants alone in preventing systemic embolism in patients with prosthetic heart valves. Dipyridamole in combination with oral anticoagulants reduces the incidence of systemic embolism after prosthetic heart valve replacement. Sulfinpyrazone reduces the incidence of sudden death in the first year after myocardial infarction, decreases the incidence of arteriovenous shunt thrombosis in patients undergoing chronic hemodialysis, and when combined with anticoagulants, may be effective in reducing the frequency of episodes in recurrent venous thrombosis.

Anticoagulants↗
PubMedDate not supplied

Experimental regional cerebral ischemia in the middle cerebral artery territory in primates. Part 3: effects on brain water and electrolytes in the late phase of acute MCA stroke.

Experimental regional cerebral ischemia was produced in the middle cerebral artery (MCA) territory in primates (M. mulatta) by macrosphere embolization. Determinations of percentage tissue dry weight and tissue sodium and potassium concentrations were obtained in samples from the ischemic and non-ischemic hemispheres at various time from 12 to 48 hours after the onset of cerebral ischemia. Samples from the cortex normally supplied by the occluded MCA showed maximal accumulation of edema fluid with fluxes in sodium and potassium in reciprocal directions at 12 hours and similar edematous changes in putamen at 24 hours after embolization By 48 hours after MCA occlusion and despite the presence of infarction, partial reversal was observed in the redistribution of water and electrolytes in these gray matter structures. In contrast to cerebral cortex and putamen, the adjacent subcortical white matter showed progressive increases in water content from 12 to 48 hours and definite increases in tissue sodium with decreases in potassium were not observed until 48 hours after MCA occlusion. This late severe white matter edema associated with cerebral infarction appears to be a major factor responsible for the hemispheric swelling observed at this state.

Animals↗
PubMed1979

Alterations in cortical oxygen tension during the development of ischemic cerebral edema in primates (Macaca mulatta).

With a closed head primate stroke model, acute cerebral ischemia limited to the middle cerebral artery (MCA) territory was produced by macrosphere embolization of the internal carotid artery bifurcation. Measurements of the oxygen tension (PO2) at the cerebral cortical surface were obtained by continuous on-line mass spectrometry. Percentage of dry weight and tissue sodium, potassium, and chloride concentrations from ischemic and nonischemic hemispheres were determined at various times. With this preparation, we registered the precise onset of cortical surface PO2 depletion, which showed an exponential downward trend (fast component from 0 to 5 minutes, t 1/2 = 0.8 minute, rate of change = 89% per minute; slow component from 5 to 240 minutes, t 1/2 = 285 minutes, rate of change = 0.3% per minute). After the onset of cerebral ischemia, there was an immediate fall of the cortical surface PO2 with reductions of more than 45% at 5 minutes before definite hemiparesis and electroencephalographic abnormalities were recognized. During the secondary phase from 5 to 240 minutes the cortical surface PO2 fell by only an additional 23% of the steady state. Even so, when cortical surface PO2 was maintained at this critically low level, the earliest cerebral cortical edema was evident 180 minutes after MCA occlusion. Thereafter, progressive accumulation of edema fluid in the cortex (90 to 170.8 microliters per g of tissue) and in the white matter (19 to 46.2 microliter per g of tissue) was detected by the end of 240 minutes of cerebral ischemia.

Animals↗