Citations

Introduction: The first-pass effect (FPE), defined as a complete or near-complete recanalization after a single pass of a mechanical thrombectomy (MT) device, has been linked to favorable clinical outcomes. However, its effectiveness in acute ischemic stroke (AIS) patients with low ASPECTS (Alberta Stroke Program Early CT Score 2-5) has not been validated. Method: We utilized data from STAR, a multicenter database of 84 centers worldwide, to conduct a retrospective, cohort study on patients who underwent MT for internal carotid artery (ICA) or M1 occlusion presenting with ASPECTS 2-5. We compared the outcomes of patients who achieved FPE (successful recanalization with an mTICI score of 2c or higher in one pass) to those who did not. The primary outcome was a 90-day favorable outcome, defined as mRS 0-3. Secondary outcomes included any intracranial hemorrhage (ICH), symptomatic ICH (sICH), and 90-day mortality. Results: Out of 10,229 patients in the STAR database, 250 patients met our inclusion criteria. Among those, 60 (24%) achieved FPE. There were no significant differences between the two groups in baseline, imaging, and procedural characteristics. FPE was significantly associated with higher odds of 90-day mRS 0-3 (adjusted odds ratio (aOR): 2.17, 95% confidence interval (CI): 1.04 - 4.20; P-value: 0.04) and lower rates of ICH (OR: 0.49, 95% CI: 0.25 - 0.93, P-value: 0.03). However, there was no significant difference in sICH rates (OR: 0.84, 95% CI: 0.31 - 2.04, P-value: 0.70). Conclusion: Achieving FPE in AIS stroke patients with low ASPECTS was associated with significantly higher rates of good functional outcomes and lower rates of ICH.

Introduction: Real-world data showed that less than half of the acute ischemic stroke (AIS) patients with large vessel occlusion (LVO) presenting with low Alberta Stroke Program Early Computed Tomography Score (ASPECTS) (2-5) achieved favorable outcomes at 90 days after mechanical thrombectomy (MT). In this study, we aim to investigate the relationship between the number of MT passes at which successful recanalization is obtained and outcomes in LVO-related AIS patients with low ASPECTS. Methods: This retrospective cohort study was performed on the data from 31 thrombectomy-capable centers between 2013 to 2022. Successful recanalization was defined as modified Thrombolysis in Cerebral Ischemia Score≥ 2b. The primary outcome was a 90-day modified Rankin Scale (mRS) of 0-3. Secondary outcomes were symptomatic intracranial hemorrhage and intracranial hemorrhage within 24 hours and mortality at 90 days. Outcomes were compared among patients with unsuccessful recanalization, and successful recanalization at first, second, third, and more than four passes. Results: A total of 297 patients with a median age of 70 [IQR 59-78] years were included and 140 (47.1%) were female. In 239 (80.4%) patients, successful recanalization was achieved: 88 patients (29.6 %) with 1 pass, 59 patients (19.9 %) with 2 passes, 35 patients(11.8%) with 3 passes, and 57 patients (19.2%) with more than 4 passes. Compared to unsuccessful recanalization, successful recanalization at first pass (adjusted OR 5.25, 95% CI 1.78 - 17.1), second passes (adjusted OR 5.20, 95% CI 1.68 - 17.6), and passes 4 (adjusted OR 4.90, 95% CI 1.68 - 17.6) was related to 90-day mRS 0-3. Recanalization status and MT attempt number were not related to secondary outcomes except for 90-day mortality. Compared to unsuccessful recanalization, successful recanalization at second and third passes were inversely related to 90-day mortality (adjusted OR 0.37, 95% CI 0.14 - 0.93; adjusted OR 0.33, 95% CI 0.11 - 0.95, respectively). Conclusion: The present results indicated that successful recanalization was related to 90-day good outcome regardless of the number of MT passes but the odds of achieving favorable outcome declines with each pass.

Introduction: The combination of intravenous or intra-arterial thrombolysis with mechanical thrombectomy (MT) for acute ischemic stroke (AIS) has been thoroughly investigated. However, no study has explored the outcomes of combining both intravenous and intra-arterial thrombolysis with MT. Methods: Data from Stroke Thrombectomy and Aneurysm Registry (STAR) from 2013 to 2023 was utilized. We compared AIS patients with LVO who underwent MT with combined intra-venous and intra-arterial thrombolysis (IV+IA) and with intra-venous thrombolysis alone (IV). We performed propensity score (PS) matching between the two groups using age, sex, premorbid mRS, admission NIHSS, occluded vessel, ASPECTS score, time from symptoms onset to arterial puncture, and frontline technique. Primary outcomes were any intracranial hemorrhage (ICH) and symptomatic ICH (sICH). Secondary outcomes included successful recanalization (mTICI ≥2C), early neurological improvement (defined as 4 or more points improvement in NIHSS score in 24 hours), 90-day modified Rankin Scale (mRS) 0-2, mRS 0-1, and mortality. Results: A total of 2495 LVO-related AIS patients were included, consisting of the IA+IV group (n = 266) and the IV group (n = 2228). Propensity matching yielded 192 well-matched patients in each group. No significant differences were observed between the groups in either ICH or sICH (odds ratio [OR]: 0.96, 95% confidence interval [CI]: 0.61-1.52, p = 0.60; OR: 0.92, 95% CI: 0.42-2.03, p > 0.90, respectively). The IA+IV group had a significantly lower proportion of successful recanalization (OR: 0.41, 95% CI: 0.27-0.62, p < 0.001), and early neurological improvement (OR: 0.55, 95% CI: 0.30-1.00). However, 90-day mRS 0-2, mRS 0-1, and mortality rates showed no significant differences between the two groups. Conclusion: The findings of this study suggest that the combined use of IA and IV thrombolysis in AIS patients undergoing MT is safe. Although the IA+IV group demonstrated lower rates of recanalization and early neurological improvement, long-term functional outcomes and mortality rates were comparable to the IV-thrombolysis group, indicating a potential delayed benefit of additional IA thrombolysis therapy.

Introduction: While balloon guide catheters (BGCs) enhance safety and efficacy of mechanical thrombectomy in large vessel occlusions, their impact on distal medium vessel occlusion (DMVO) remains underexplored. This study aimed to compare the outcomes of BGC vs non-BGC in DMVO thrombectomy. Methods: This retrospective study focused on DMVO cases defined as occlusions in M2-M4 middle cerebral artery, anterior cerebral artery, and posterior cerebral artery. Baseline characteristics and technical and clinical outcomes were compared between the two groups, with subgroup analysis in first-line thrombectomy techniques, including ADAPT, stent retriever, and Solumbra. First pass effect (FPE) was defined as a modified Thrombolysis in Cerebral Infarction (mTICI) score ≥ 2C after the first pass. Results: A total of 1,508 patients were included, of whom 231 (15.3%) were in the BGC group and 1,277 (84.7%) were in the Non-BGC group. The BGC group was associated with a lower mTICI score ≥ 2C (overall: 43.2% vs. 52.7%, p = 0.01; ADAPT: 42.2% vs. 57.1%, p = 0.01; Solumbra: 32.4% vs. 51.4%, p = 0.005), longer puncture to intracranial access time (overall: 15 vs. 8 min, p < 0.001; ADAPT: 17 vs. 8 min, p < 0.001; Solumbra: 12 vs. 8 min, p = 0.02), and longer puncture to recanalization time (overall: 97 vs. 35 min, p < 0.001; ADAPT: 100 vs. 28 min, p < 0.001; Solumbra: 78 vs. 46 min, p < 0.001; Stent retriever: 95 vs. 45 min, p < 0.001 ). The BGC group also had a lower FPE rate (17.4% vs. 30.7%, p = 0.03) in the Solumbra subgroup. In terms of clinical outcomes, the BGC group had a lower rate of distal embolization (overall: 8.8% vs. 14.9%, p = 0.02), but there were no significant differences in other clinical outcomes between the two groups in first-line thrombectomy techniques. Conclusions: Our findings showed that the use of BGC in DMVO had a lower mTICI score, reduced FPE rates, decreased distal embolization, and longer procedure times. Figure 1: Figure 2:

Introduction: The efficacy of mechanical thrombectomy (MT) for tandem vertebrobasilar occlusion (tVBO) is not well established in patients with basilar artery occlusion (BAO). Objective: To investigate the treatment outcomes of MT in tVBO. Method: This international, multicenter, retrospective cohort included patients with MT for tVBO and isolated BAO from 2013 to 2023. The primary outcome was the 90-day modified Rankin Scale (mRS) score 0-2. Secondary outcomes included complete recanalization (modified Thrombolysis in Cerebral Ischemia [mTICI] ≥ 2C) and 90-day mortality rate. These outcomes were compared between tVBO and isolated BAO groups. Adjustment factors were age, sex, admission National Institutes of Health Stroke Scale (NIHSS), pre-morbid mRS, onset to groin duration, and intravenous tissue plasminogen activator. Results: Among 10,229 patients, 689 had BAO. Of those, 61 (9.7%) had a tVBO. Median age was 61 [IQR 53-74] years and 29 (47.5%) patients were female. Compared to isolated BAO, tVBO group had lower age (61 [53-74] versus 68 [58-79], P<0.001) and lower admission NIHSS (15 [7 - 22] versus 17 [9-26], P≤0.05). There was no significant difference in the rate of complete recanalization between the two groups (adjusted odds ratio [aOR]: 0.83; 95% CI: 0.39-1.79; P=0.60) However, the tVBO group had significantly lower odds of a favorable outcome compared to the isolated BAO group (aOR: 0.35; 95% CI: 0.13-0.83; P=0.023) and higher odds of 90-day mortality (aOR: 3.51; 95% CI: 1.59-7.85; P=0.002). Binary regression analysis revealed that age (OR 0.98; 95% CI 0.96 - 1.00; P=0.019), admission NIHSS (OR 0.90; 95% CI 0.87-0.93; P<0.001), premorbid mRS (OR 0.71; 95% CI 0.53-0.93; P=0.016), successful recanalization (OR 2.94; 95% CI 1.71-5.15; P<0.001), and tVBO (OR 0.33; 95% CI 0.11-0.86; P=0.031) were significant predictors of 90-day favorable outcome. Conclusion: tVBO was associated with poor outcomes. Further efforts should be aimed at improving outcomes for this subpopulation.

Objective: To determine whether first pass effect (FPE) after mechanical thrombectomy (MT) for anterior circulation large vessel occlusion acute ischemic stroke (LVO-AIS) is modified by procedural time (PT). Methods: The Stroke Thrombectomy and Aneurysm Registry (STAR), a multi-center international dataset, was retrospectively analyzed for anterior circulation LVO-AIS treated by MT who achieved excellent reperfusion (TICI 2c/3). The primary outcome was good functional outcome as defined by a 90-day modified Rankin Scale (mRS) 0-2. The primary study exposure was first pass success (FPS, 1 pass vs ≥2 passes) and the secondary exposure was PT. Logistic regression models were fit-adjusted and marginal effects used to assess the interaction of PT (≤30 vs >30 minutes) and FPS, adjusting for potential confounders including time from last known well to start of MT. Results: A total of 1,310 patients had excellent reperfusion. These patients were divided into two cohorts based on PT: ≤30 minutes (777 patients, 59.3%) and > 30 minutes (533 patients, 40.7%). Good functional outcome was observed in 658 patients (50.2%). The interaction term between FPS and PT was significant (p=0.018). Individuals with FPS in ≤30 minutes had 11.5% higher adjusted predicted probability of good outcome compared with those who required ≥2 passes (58.2% vs. 46.7%, p=0.001). However, there was no significant difference in the adjusted predicted probability of good outcome based on FPS in individuals with PT >30 minutes (p=0.763). This relationship appeared identical in models with PT treated as a continuous variable. Conclusion: In a large, real-world, multi-national dataset, we find that FPE is importantly modified by PT. The added clinical benefit of FPE is lost in longer procedures (>30 minutes). These data argue for a new metric for MT procedures, namely, FPE 30 , that better represents the ideal of fast, complete reperfusion with a single pass of a thrombectomy device.

Importance Germline gene panel testing is recommended for men with advanced prostate cancer (PCa) or a family history of cancer. While evidence is limited for some genes currently included in panel testing, gene panels are also likely to be incomplete and missing genes that influence PCa risk and aggressive disease. Objective To identify genes associated with aggressive PCa. Design, Setting, and Participants A 2-stage exome sequencing case-only genetic association study was conducted including men of European ancestry from 18 international studies. Data analysis was performed from January 2021 to March 2023. Participants were 9185 men with aggressive PCa (including 6033 who died of PCa and 2397 with confirmed metastasis) and 8361 men with nonaggressive PCa. Exposure Sequencing data were evaluated exome-wide and in a focused investigation of 29 DNA repair pathway and cancer susceptibility genes, many of which are included on gene panels. Main Outcomes and Measures The primary study outcomes were aggressive (category T4 or both T3 and Gleason score ≥8 tumors, metastatic PCa, or PCa death) vs nonaggressive PCa (category T1 or T2 and Gleason score ≤6 tumors without known recurrence), and metastatic vs nonaggressive PCa. Results A total of 17 546 men of European ancestry were included in the analyses; mean (SD) age at diagnosis was 65.1 (9.2) years in patients with aggressive PCa and 63.7 (8.0) years in those with nonaggressive disease. The strongest evidence of association with aggressive or metastatic PCa was noted for rare deleterious variants in known PCa risk genes BRCA2 and ATM ( P ≤ 1.9 × 10 −6 ), followed by NBN ( P = 1.7 × 10 −4 ). This study found nominal evidence ( P &amp;lt; .05) of association with rare deleterious variants in MSH2 , XRCC2 , and MRE11A . Five other genes had evidence of greater risk (OR≥2) but carrier frequency differences between aggressive and nonaggressive PCa were not statistically significant: TP53 , RAD51D , BARD1 , GEN1 , and SLX4 . Deleterious variants in these 11 candidate genes were carried by 2.3% of patients with nonaggressive, 5.6% with aggressive, and 7.0% with metastatic PCa. Conclusions and Relevance The findings of this study provide further support for DNA repair and cancer susceptibility genes to better inform disease management in men with PCa and for extending testing to men with nonaggressive disease, as men carrying deleterious alleles in these genes are likely to develop more advanced disease.

Importance Radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS) punctuated by incidental magnetic resonance imaging (MRI) white matter anomalies within the central nervous system. Objective To determine the time to onset of symptoms consistent with MS. Design, Setting, and Participants From September 2017 to October 2022, this multicenter, double-blind, phase 3, randomized clinical trial investigated the efficacy of teriflunomide in delaying MS in individuals with RIS, with a 3-year follow-up. The setting included referral centers in France, Switzerland, and Turkey. Participants older than 18 years meeting 2009 RIS criteria were randomly assigned (1:1) to oral teriflunomide, 14 mg daily, or placebo up to week 96 or, optionally, to week 144. Interventions Clinical, MRI, and patient-reported outcomes (PROs) were collected at baseline and yearly until week 96, with an optional third year in the allocated arm if no symptoms have occurred. Main outcomes Primary analysis was performed in the intention-to-treat population, and safety was assessed accordingly. Secondary end points included MRI outcomes and PROs. Results Among 124 individuals assessed for eligibility, 35 were excluded for declining to participate, not meeting inclusion criteria, or loss of follow-up. Eighty-nine participants (mean [SD] age, 37.8 [12.1] years; 63 female [70.8%]) were enrolled (placebo, 45 [50.6%]; teriflunomide, 44 [49.4%]). Eighteen participants (placebo, 9 [50.0%]; teriflunomide, 9 [50.0%]) discontinued the study, resulting in a dropout rate of 20% for adverse events (3 [16.7%]), consent withdrawal (4 [22.2%]), loss to follow-up (5 [27.8%]), voluntary withdrawal (4 [22.2%]), pregnancy (1 [5.6%]), and study termination (1 [5.6%]). The time to the first clinical event was significantly extended in the teriflunomide arm compared with placebo, in both the unadjusted (hazard ratio [HR], 0.37; 95% CI, 0.16-0.84; P = .02) and adjusted (HR, 0.28; 95% CI, 0.11-0.71; P = .007) analysis. Secondary imaging end point outcomes including the comparison of the cumulative number of new or newly enlarging T2 lesions (rate ratio [RR], 0.57; 95% CI, 0.27-1.20; P = .14), new gadolinium-enhancing lesions (RR, 0.33; 95% CI, 0.09-1.17; P = .09), and the proportion of participants with new lesions (odds ratio, 0.72; 95% CI, 0.25-2.06; P = .54) were not significant. Conclusion and Relevance Treatment with teriflunomide resulted in an unadjusted risk reduction of 63% and an adjusted risk reduction of 72%, relative to placebo, in preventing a first clinical demyelinating event. These data suggest a benefit to early treatment in the MS disease spectrum. Trial Registration ClinicalTrials.gov Identifier: NCT03122652

HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22–1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04–1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35–1.73, p < 0.001), microvascular (HR = 2.37, 95%–CI, 1.87–2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41–4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29–2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54–3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.