Citations

Background: Acute ischemic stroke (AIS) from primary medium vessel occlusions (MeVO) is a prevalent condition associated with substantial morbidity and mortality. Despite the common use of mechanical thrombectomy (MT) in AIS, predictors of poor outcomes in MeVO remain poorly characterized. Methods: In this prospectively collected, retrospectively reviewed, multicenter, multinational study, data from the MAD-MT (Multicenter Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy) registry were analyzed. The study included 1568 patients from 37 academic centers across North America, Asia, and Europe, treated with MT, with or without intravenous tissue plasminogen activator (IVtPA), between September 2017 and July 2021. Results: Among the 1568 patients, 347 (22.2%) experienced very poor outcomes (modified Rankin score (mRS), 5–6). Key predictors of poor outcomes were advanced age (odds ratio (OR): 1.03; 95% confidence interval (CI): 1.02 to 1.04; p < 0.001), higher baseline National Institutes of Health Stroke Scale (NIHSS) scores (OR: 1.07; 95% CI: 1.05 to 1.10; p < 0.001), pre-operative glucose levels (OR: 1.01; 95% CI: 1.00 to 1.02; p < 0.001), and a baseline mRS of 4 (OR: 2.69; 95% CI: 1.25 to 5.82; p = 0.011). The multivariable model demonstrated good predictive accuracy with an area under the receiver-operating characteristic (ROC) curve of 0.76. Conclusions: This study demonstrates that advanced age, higher NIHSS scores, elevated pre-stroke mRS, and pre-operative glucose levels significantly predict very poor outcomes in AIS-MeVO patients who received MT. These findings highlight the importance of a comprehensive risk assessment in primary MeVO patients for personalized treatment strategies. However, they also suggest a need for cautious patient selection for endovascular thrombectomy. Further prospective studies are needed to confirm these findings and explore targeted therapeutic interventions.

Background Acute ischemic stroke (AIS) caused by distal medium vessel occlusions (DMVOs) represents a significant proportion of overall stroke cases. While intravenous thrombolysis (IVT) has been a primary treatment, advancements in endovascular procedures have led to increased use of mechanical thrombectomy (MT) in DMVO stroke patients. However, symptomatic intracerebral hemorrhage (sICH) remains a critical complication of AIS, particularly after undergoing intervention. This study aims to identify factors associated with sICH in DMVO stroke patients undergoing MT. Methods This retrospective analysis utilized data from the Multicenter Analysis of Distal Medium Vessel Occlusions: Effect of Mechanical Thrombectomy (MAD-MT) registry, involving 37 centers across North America, Asia, and Europe. Middle cerebral artery (MCA) DMVO stroke patients were included. The primary outcome measured was sICH, as defined per the Heidelberg Bleeding Classification. Univariable and multivariable logistic regression were used to identify factors independently associated with sICH. Results Among 1708 DMVO stroke patients, 148 (8.7%) developed sICH. Factors associated with sICH in DMVO patients treated with MT included older age (adjusted odds ratio (aOR) 1.01, 95% confidence interval (95% CI) 1.00 to 1.03, P=0.048), distal occlusion site (M3, M4) compared with medium occlusions (M2) (aOR 1.71, 95% CI 1.07 to 2.74, P=0.026), prior use of antiplatelet drugs (aOR 2.06, 95% CI 1.41 to 2.99, P<0.001), lower Alberta Stroke Program Early CT Scores (ASPECTS) (aOR 0.75, 95% CI 0.66 to 0.84, P<0.001), higher preoperative blood glucose level (aOR 1.00, 95% CI 1.00 to 1.01, P=0.012), number of passes (aOR 1.27, 95% CI 1.15 to 1.39, P<0.001), and successful recanalization (Thrombolysis In Cerebral Infarction (TICI) 2b-3) (aOR 0.43, 95% CI 0.28 to 0.66, P<0.001). Conclusion This study provides novel insight into factors associated with sICH in patients undergoing MT for DMVO, emphasizing the importance of age, distal occlusion site, prior use of antiplatelet drugs, lower ASPECTS, higher preoperative blood glucose level, and procedural factors such as the number of passes and successful recanalization. Pending confirmation, consideration of these factors may improve personalized treatment strategies.

6574 Background: Pts with MF experience debilitating symptoms that negatively impact health-related quality of life (HRQOL), a burden compounded in those with anemia. Prior analysis of the phase 3 SIMPLIFY-1 (S1) and SIMPLIFY-2 (S2) trials found that achieving transfusion independence at wk 24 was associated with improved PROs, but the association of anemia severity by Hb level with PROs was inconclusive (Mesa, ASCO 2023, Poster 7066). This new post hoc analysis explored the impact of Hb improvement on PROs in pts with MF and anemia. Methods: The pooled treatment-agnostic analysis set included pts with anemia (baseline [BL] Hb <10 g/dL) from 3 phase 3 trials: S1 (JAK inhibitor [JAKi] naive; MMB vs ruxolitinib), S2 (JAKi experienced; MMB vs best available therapy), and MOMENTUM (JAKi experienced; MMB vs danazol). The EQ-5D-5L was administered, and health state index (UK value set) and visual analog scale (VAS) scores derived, in all 3 trials. Patient Global Impression of Change (PGIC) was administered in S1/S2. Hb improvement was defined as an increase of ≥1, ≥1.5, or ≥2 g/dL from BL at wk 24. Multivariate (MV) analyses included change in EQ-5D-5L scores from BL as the dependent variable, with wk 24 Hb improvement and key BL characteristics as independent variables. Results: Mean age of the anemic subpopulation (N=480) was 68.8 y; 62% were male, 81% were White, and 64% had primary MF.436 pts were evaluable for Hb improvement at wk 24; 298 and 297 were evaluable for EQ-5D-5L index and VAS scores, respectively. Mean improvements from BL in index and VAS scores were greater in pts who achieved Hb improvement at any threshold than in those who did not (Table). 241 pts were evaluable for Hb improvement at wk 24 in S1/S2; 215 were evaluable for PGIC. Hb improvement was associated with a higher percentage of pts with any symptom improvement and lower percentage with symptom worsening based on PGIC (Table). In MV analyses, Hb improvement at any threshold was significantly associated with positive change in EQ-5D-5L VAS scores at wk 24 (mean change estimates of 5.5 to 7.3); similar trends were observed in MV analyses for EQ-5D-5L index scores. Conclusions: In these trial populations, Hb improvement at wk 24 was associated with improved HRQOL and symptoms in pts with MF and anemia. These results highlight the value of treatments with anemia-related benefits in improving the pt experience in MF. Clinical trial information: NCT04173494 ; NCT02101268 ; NCT01969838 . [Table: see text]

Importance Sudden death and cardiac arrest frequently occur without explanation, even after a thorough clinical evaluation. Calcium release deficiency syndrome (CRDS), a life-threatening genetic arrhythmia syndrome, is undetectable with standard testing and leads to unexplained cardiac arrest. Objective To explore the cardiac repolarization response on an electrocardiogram after brief tachycardia and a pause as a clinical diagnostic test for CRDS. Design, Setting, and Participants An international, multicenter, case-control study including individual cases of CRDS, 3 patient control groups (individuals with suspected supraventricular tachycardia; survivors of unexplained cardiac arrest [UCA]; and individuals with genotype-positive catecholaminergic polymorphic ventricular tachycardia [CPVT]), and genetic mouse models (CRDS, wild type, and CPVT were used to define the cellular mechanism) conducted at 10 centers in 7 countries. Patient tracings were recorded between June 2005 and December 2023, and the analyses were performed from April 2023 to December 2023. Intervention Brief tachycardia and a subsequent pause (either spontaneous or mediated through cardiac pacing). Main Outcomes and Measures Change in QT interval and change in T-wave amplitude (defined as the difference between their absolute values on the postpause sinus beat and the last beat prior to tachycardia). Results Among 10 case patients with CRDS, 45 control patients with suspected supraventricular tachycardia, 10 control patients who experienced UCA, and 3 control patients with genotype-positive CPVT, the median change in T-wave amplitude on the postpause sinus beat (after brief ventricular tachycardia at ≥150 beats/min) was higher in patients with CRDS ( P &amp;lt; .001). The smallest change in T-wave amplitude was 0.250 mV for a CRDS case patient compared with the largest change in T-wave amplitude of 0.160 mV for a control patient, indicating 100% discrimination. Although the median change in QT interval was longer in CRDS cases ( P = .002), an overlap between the cases and controls was present. The genetic mouse models recapitulated the findings observed in humans and suggested the repolarization response was secondary to a pathologically large systolic release of calcium from the sarcoplasmic reticulum. Conclusions and Relevance There is a unique repolarization response on an electrocardiogram after provocation with brief tachycardia and a subsequent pause in CRDS cases and mouse models, which is absent from the controls. If these findings are confirmed in larger studies, this easy to perform maneuver may serve as an effective clinical diagnostic test for CRDS and become an important part of the evaluation of cardiac arrest.

Importance Neurological manifestations during acute SARS-CoV-2–related multisystem inflammatory syndrome in children (MIS-C) are common in hospitalized patients younger than 18 years and may increase risk of new neurocognitive or functional morbidity. Objective To assess the association of severe neurological manifestations during a SARS-CoV-2–related hospital admission with new neurocognitive or functional morbidities at discharge. Design, Setting, and Participants This prospective cohort study from 46 centers in 10 countries included patients younger than 18 years who were hospitalized for acute SARS-CoV-2 or MIS-C between January 2, 2020, and July 31, 2021. Exposure Severe neurological manifestations, which included acute encephalopathy, seizures or status epilepticus, meningitis or encephalitis, sympathetic storming or dysautonomia, cardiac arrest, coma, delirium, and stroke. Main Outcomes and Measures The primary outcome was new neurocognitive (based on the Pediatric Cerebral Performance Category scale) and/or functional (based on the Functional Status Scale) morbidity at hospital discharge. Multivariable logistic regression analyses were performed to examine the association of severe neurological manifestations with new morbidity in each SARS-CoV-2–related condition. Results Overall, 3568 patients younger than 18 years (median age, 8 years [IQR, 1-14 years]; 54.3% male) were included in this study. Most (2980 [83.5%]) had acute SARS-CoV-2; the remainder (588 [16.5%]) had MIS-C. Among the patients with acute SARS-CoV-2, 536 (18.0%) had a severe neurological manifestation during hospitalization, as did 146 patients with MIS-C (24.8%). Among survivors with acute SARS-CoV-2, those with severe neurological manifestations were more likely to have new neurocognitive or functional morbidity at hospital discharge compared with those without severe neurological manifestations (27.7% [n = 142] vs 14.6% [n = 356]; P &amp;lt; .001). For survivors with MIS-C, 28.0% (n = 39) with severe neurological manifestations had new neurocognitive and/or functional morbidity at hospital discharge compared with 15.5% (n = 68) of those without severe neurological manifestations ( P = .002). When adjusting for risk factors in those with severe neurological manifestations, both patients with acute SARS-CoV-2 (odds ratio, 1.85 [95% CI, 1.27-2.70]; P = .001) and those with MIS-C (odds ratio, 2.18 [95% CI, 1.22-3.89]; P = .009) had higher odds of having new neurocognitive and/or functional morbidity at hospital discharge. Conclusions and Relevance The results of this study suggest that children and adolescents with acute SARS-CoV-2 or MIS-C and severe neurological manifestations may be at high risk for long-term impairment and may benefit from screening and early intervention to assist recovery.

Abstract Background: Stroke remains a major health concern globally, with oral anticoagulants widely prescribed for stroke prevention. The efficacy and safety of mechanical thrombectomy (MT) in anticoagulated patients with distal medium vessel occlusions (DMVO) are not well understood. Methods: This retrospective analysis involved 1282 acute ischemic stroke (AIS) patients who underwent MT in 37 centers across North America, Asia, and Europe from September 2017 to July 2023. Data on demographics, clinical presentation, treatment specifics, and outcomes were collected. The primary outcomes were functional outcomes at 90 days post-MT, measured by modified Rankin Scale (mRS) scores. Secondary outcomes included reperfusion rates, mortality, and hemorrhagic complications. Results: Of the patients, 223 (34%) were on anticoagulation therapy. Anticoagulated patients were older (median age 78 vs 74 years; p &lt; 0.001) and had a higher prevalence of atrial fibrillation (77% vs 26%; p &lt; 0.001). Their baseline National Institutes of Health Stroke Scale (NIHSS) scores were also higher (median 12 vs 9; p = 0.002). Before propensity score matching (PSM), anticoagulated patients had similar rates of favorable 90-day outcomes (mRS 0–1: 30% vs 37%, p = 0.1; mRS 0–2: 47% vs 50%, p = 0.41) but higher mortality (26% vs 17%, p = 0.008). After PSM, there were no significant differences in outcomes between the two groups. Conclusion: Anticoagulated patients undergoing MT for AIS due to DMVO did not show significant differences in 90-day mRS outcomes, reperfusion, or hemorrhage compared to non-anticoagulated patients after adjustment for covariates.

Introduction- Two dimensional speckle tracking echocardiography is a novel non-invasive method to assess subtle changes in left ventricular (LV) function such as strain and rotational dynamics. Limited data exists for assessing the impact of severity of aortic stenosis (AS) on LV apical rotation Objective- To determine the impact of severity of AS on LV longitudinal strain as well as LV apical rotation in patients with preserved LV ejection fraction and various degrees of AS. Methods- We prospectively measured longitudinal LV strain and apical rotation in 74patients with preserved LV ejection fraction but no (n= 22), mild (MG 10-25 mmHg; n= 20), moderate (MG 25-40 mmHg; n= 18), or severe (MG >40 mmHg; n= 14) AS who were undergoing echocardiographic examination at our institution. Two dimensional speckle tracking method was used to obtain average peak longitudinal strain using apical 4, 2-chamber and long-axis views while apical short axis view was used to obtain the LV apical rotation. Results- Mean age between no vs. mild vs. mod vs. severe AS groups (73±11yrs; 70±13yrs; 77±6yrs; 76±14 yrs) was not different (p=0.26). Presence of hypertension (64%, 65%, 78%, 71%) and coronary artery disease (14%, 6%, 25%, 29%) were also not different between the groups (p = 0.76 and p = 0.23 respectively). Average LV peak global longitudinal strain was not different between groups (-17.5±3%; -17.5±5%;-16.6±4%; -16.6±3% (p=0.82). However LV peak apical rotation was higher with worsening severity of aortic stenosis (14.8±8°; 14.7±9°; 21.3±11°; 23.7±12°) (overall p=0.02) (Figure). Conclusions- 1) LV peak longitudinal strain was not different between patients with no stenosis when compared to patients with various levels of aortic stenosis. 2) However, LV apical rotation increases with worsening levels of AS probably to maintain the LV stroke volume. Further studies are needed to evaluate the role of LV apical rotation in deciding the timing of surgery in patients with severe AS.

Introduction- Recent studies based on echocardiographic data have described an entity termed paradoxical low-flow, low-gradient severe aortic stenosis (AS) with preserved ejection fraction (EF). It is not clear whether this condition is also seen in patients who undergo hemodynamic catheterization. Objective- To determine the prevalence of low-flow in patients with low mean gradient (MG) severe AS despite preserved EF as determined by echocardiography who subsequently undergo hemodynamic catheterization. Methods- We retrospectively reviewed medical records of 259 patients who underwent hemodynamic catheterization at Mayo Clinic from 2000-2009 to assess the severity of AS within 6 months of their echocardiographic study. Results- A total of 35 patients (mean age 75±9yrs; 49% males) had MG (≤ 40 mm Hg) and aortic valve area (AVA ≤ 1 cm2) despite preserved EF (≥50%) as determined by echocardiography. A total of 7/35 patients (20%) had low flow by echocardiography, defined as stroke volume index (SVI) ≤ 35 ml/m2 (median SVI of 32 ml/m2, inter-quartile range 30-33 ml/m2). Among the same 35 patients, there were 23 patients who had both low MG (≤ 40 mm Hg) and severe AS (AVA ≤ 1 cm2), while a total of 14/35 patients (40%) had low MG, severe AS as well as low flow (median SVI of 32 ml/m2, inter-quartile range 29-33 ml/m2) as determined by hemodynamic catheterization. A statistically significant correlation with modest association was observed between invasive and noninvasive measurements of MG, SVI, and AVA (r=0.48 ; p = 0.003; r=0.48; p = 0.004 ; r=0.36; p=0.03 respectively) in our study group of 35 patients. In most patients (94%) MG by catheterization was also ≤ 40 mm Hg. However, agreement between echocardiography and catheterization to identify patients with paradoxical low-flow, low MG, severe AS was poor (kappa = 0.03). Conclusions- 1) Paradoxical low flow, low-gradient severe aortic stenosis is also observed in patients who undergo hemodynamic catheterization. 2) Further studies are needed to better understand the pathophysiology, best method for diagnosis and true prevalence of this entity.

Abstract Lung cancer is the leading cause of cancer-related deaths worldwide. Existing therapeutic options have limited efficacy, underscoring the critical need for the identification of new actionable therapeutic targets. We previously identified the Transmembrane Serine Protease TMPRSS11B as a novel gene that promotes the transformation of human bronchial epithelial cells in vitro and induces tumorigenesis in vivo. TMPRSS11B promotes extracellular release of Basigin, an obligate chaperone of the lactate monocarboxylate transporters MCT1/4, enhancing lactate export and glycolytic metabolism, and thereby promoting tumorigenesis. Importantly, TMPRSS11B is frequently overexpressed in human lung squamous cell cancers (LSCC) and high expression is associated with poor patient survival. Moreover, as a cell surface protein and enzyme, TMPRSS11B represents a tractable target for therapeutic intervention. To investigate whether TMPRSS11B activity impacts the host immune system and the tumor microenvironment (TME), we evaluated the effect of Tmprss11b depletion in a syngeneic LSCC mouse model, KLN205. Tmprss11b loss of function in KLN205 LSCC cells significantly reduced tumor burden in immunocompetent mice and triggered an accumulation of CD4+ T cells. We are currently extending these studies by investigating the effect of Tmprss11b loss of function using CRISPR/Cas9 editing in the Rosa26LSL-Sox2-IRES-GFP; Nkx2-1 fl/fl; Lkb1fl/fl (SNL) mouse model of LSCC. Tumor burden analysis and pH-sensitive fluorescent imaging are ongoing to assess changes in lactate accumulation. Moreover, RNA FISH analysis and spatial transcriptomics revealed that Tmprss11b expression is highly enriched in lung squamous tumors compared to lung adenocarcinomas and normal lung in SNL mice. Spatial analysis of the transcriptome is currently ongoing to assess the effects of Tmprss11b expression on the TME. Collectively, these studies will elucidate the molecular mechanisms through which TMPRSS11B promotes tumor growth and alters the tumor microenvironment in LSCC. Citation Format: Hari Shankar Sunil, Barrett L. Updegraff, Jingfei Zhu, Lisa Thomas, Bret M. Evers, Jean R. Clemenceau, Isabel Barnfather, John D. Minna, Ralph J. Deberardinis, Trudy G. Oliver, Tae Hyun Hwang, Kathryn A. O'Donnell. Transmembrane serine protease TMPRSS11B promotes tumorigenesis in lung squamous cell carcinoma through enhanced lactate export and modulation of the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1793.