Citations

Abstract Background Recent trials have furthered uncertainty regarding the endovascular benefit for medium vessel occlusions (MeVO). Stent retrievers (SR) were employed in the first attempt in most interventional arm participants. We sought to compare outcomes in acute MCA M2 occlusions between frontline aspiration and SR, and to delineate procedural and anatomical covariates associated with differential treatment effect. Methods Retrospective analysis of a multicenter stroke thrombectomy cohort identified cases of MT for M2 occlusions. Unmatched and propensity score-matched (PSM) cohorts were generated comparing frontline aspiration to standalone and combined SR. The primary outcome was functional independence (mRS 0–2) at 90 days. Recanalization, symptomatic intracranial hemorrhage (sICH), mortality, and the effect of M2 laterality, division occlusion and procedure time were assessed. Results About 1734 patients with M2 occlusions underwent either frontline aspiration (n = 711) or SR/combined (n = 958) thrombectomy between 2013 and 2024. PSM analysis favored aspiration for functional independence (49.9% vs 44.0%, OR 1.27 (1.03–1.57)), complete recanalization (61.2% vs 48.7%, OR 1.66 (1.34–2.05)), complete first pass effect (35.0% vs 27.6%, OR 1.42 (1.13–1.78)), and sICH (3.5% vs 6.2%, OR 0.55 (0.33–0.91)), with no difference in mortality. Frontline aspiration had significantly shorter procedural times (median 28 [IQR 15–49.5] vs 51 [IQR 35–78] minutes; p < 0.001). For every minute increase in procedure time, the probability of functional independence decreased significantly (p < 0.001) less with frontline aspiration (0.35%) compared to SR/combined (1.61%). Conclusion Frontline aspiration for M2 occlusions resulted in better clinical and angiographic outcomes compared to SRs. Future trials for MeVO with a focus on contact aspiration thrombectomy may succeed where recent trials have failed.

Background Dual antiplatelet therapy (DAPT) is recommended around carotid artery stenting (CAS) to reduce periprocedural stroke risk. Clopidogrel is widely used, but response variability related to pharmacokinetics and CYP2C19 polymorphisms may limit its effectiveness. Ticagrelor is a more potent, direct acting P2Y12 inhibitor, but its comparative effectiveness in CAS remains uncertain. Methods We conducted a retrospective cohort study in the TriNetX database, identifying adults with carotid artery stenosis who underwent CAS between January 2016 and August 2025 and received either ticagrelor or clopidogrel. Primary outcomes at 180 days included ischemic stroke, major hemorrhage, intracranial hemorrhage, and all cause mortality. Secondary outcomes included inpatient readmission and emergency department (ED) visits. Propensity score matching (1:1), Kaplan–Meier survival, and Cox proportional hazards analysis were used. Results Among 6996 patients, 378 received ticagrelor and 6618 received clopidogrel; aspirin co-use was similar (89.7% vs 91.7%). After matching, 377 patients remained in each cohort. Ischemic stroke (2.7% vs 4.2%; HR 0.56, 95% CI 0.25 to 1.27; P=0.159) and major hemorrhage (2.9% vs 4.8%; HR 0.61, 95% CI 0.29 to 1.30; P=0.197) were numerically lower with ticagrelor. Rates of intracranial hemorrhage were similar (2.7% vs 2.7%; HR 0.61, 95% CI 0.14 to 2.53; P=0.488). Mortality was numerically higher with ticagrelor (3.4% vs 2.7%; HR 1.64, 95% CI 0.68 to 3.97; P=0.263). ED visits were similar (14.3% vs 14.6%; HR 0.97, 95% CI 0.67 to 1.42; P=0.895). Inpatient readmission was numerically lower with ticagrelor (15.9% vs 19.1%; HR 0.81, 95% CI 0.57 to 1.14; P=0.223). Conclusion Ticagrelor and clopidogrel showed comparable safety and effectiveness following CAS. Future prospective genotype informed trials are warranted to confirm these findings.

FRACTURE MRI demonstrated strong agreement with conventional radiography and CT in evaluating key bone tumor characteristics, including lesion type, location, and matrix content.

Abstract BACKGROUND Whilst the broad clonal architecture of naturally progressing chronic lymphocytic leukemia (CLL) has been described, a comprehensive picture of how chemotherapy and targeted agents reshape that landscape is lacking. Here we integrate clone-specific growth kinetics with mutational profiles, transcriptomic subtypes, and CpG-methylation-based epigenetic classes to capture the multidimensional evolutionary responses of CLL under native conditions and during treatment. METHODS We previously reported a systematic whole-exome sequencing (WES) analysis of 417 leukemia–germline pairs from 169 treatment-naïve patients ≥ 65 y (Karisani et al., Blood 2024). The treatment arm comprised 83 patients who received ibrutinib and 39 who received chlorambucil in the RESONATE-2 trial (NCT01722487). Forty-seven age-matched “watch-and-wait” patients from the CLL Research Consortium served as untreated controls. Peripheral-blood samples were collected at baseline and again ~300 d and ~600 d after therapy initiation (or diagnosis in the watch-and-wait cohort), enabling longitudinal clonal tracking. WES data were processed with PhylogicNDT to reconstruct clonal architectures, define phylogenies, and identify significant clonal shifts. MutSig tools identified mutations enriched in expanding or contracting clones. Pretreatment RNA-sequencing profiles were grouped into transcriptional subtypes by consensus clustering based on the Louvain algorithm. Differentially methylated regions plus epitypes were called from reduced representation bisulfite sequencing data. RESULTS Across the 169 patients with WES, we resolved 579 subclonal clusters. Significant clonal shifts (defined as a distribution shift of cancer cell fraction in a subclone of >95% between two timepoints) were uncommon during watch-and-wait (36%) but markedly higher after therapy — chlorambucil 67% (q = 0.01), and ibrutinib 77% (q < 10-4). In ibrutinib-treated CLL, regressing subclones were enriched for KRAS (q<10-3) and SF3B1 mutations (q<10-3), whereas expanding subclones preferentially harboured mutations in BIRC3 (q<10-4), NOTCH1 (q <10-3), TP53 (q=0.02), and POT1 (q=0.098). In chlorambucil-treated patients, no specific mutations were found to be enriched in expanding or regressing subclones. Using the recently defined CLL expression clusters (ECs) in patients treated with chemoimmunotherapy as defined by Knisbacher et al. (Nat Genet 2022), we were unable to identify any relationship between ECs and outcomes. We therefore sought to identify de novo ECs with prognostic relevance in the context of BTK-inhibition (BTKi-ECs). We identified a transcriptionally defined patient subgroup (C4, n=20) associated with inferior progression-free survival (median PFS = 63 months, log-rank q=0.05), independent of known prognostic clinical and molecular features, including epitypes, in multivariate analysis (Cox HR=3.7, 95% CI: 1.6-8.6, q=0.02). Gene-set enrichment in this cluster highlighted TNF-ɑ signalling via NF-κB (REL, TNFAIP3, NFKB2) and G2M checkpoint pathways (SMC4, EZH2). We also identified a distinct transcriptionally defined patient subgroup (C3, n=18) that was enriched for patients harboring at least one contracting subclone and no expanding subclones (q=0.005). This cluster showed a relative depletion of mutations within the chromatin modification pathway (6% vs 50%, q<0.01). Gene-set enrichment in this cluster highlighted a downregulation of genes in the TNF-ɑ signalling via NF-κB pathway (SOCS3, ICOSLG, NFKB2). CONCLUSION BTK inhibition and chemotherapy drive distinct evolutionary trajectories in CLL. Multi-omics profiling reveals mutation-defined subclones with divergent sensitivity to targeted therapy and delineates two informative expression states: a high-risk NF-κB/inflammatory cluster (C4; poor PFS) and a cluster enriched with contracting subclones with depleted TNF-ɑ signalling via NF-κB (C3). Integrating clonal growth kinetics with genomic, transcriptomic, and methylation data can potentially identify patients likely to progress on BTK inhibitors and identify actionable pathways for adaptive or combination therapy.

Abstract Background: For LS-DLBCL, clinical trials (FLYER, LYSA/GOELAMS 02-03, LYSA LNH09-1B, S1001) have shown that 4 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP4) without radiation (RT) leads to durable remissions in >90% of cases. However, only patients (pts) with non-bulky disease and/or international prognostic index (IPI) of 0 and complete metabolic response (CMR) on interim positron emission tomography (PET) scan, if performed, were eligible for RCHOP4 alone in these studies. Outcomes in trial-ineligible LS-DLBCL and the appropriate real-world candidates for RCHOP4 are still undefined. Methods: We conducted a multicenter retrospective study of adult pts with stage I/II DLBCL of any tumor bulk, IPI and with or without B-symptoms diagnosed after 2011 and treated with RCHOP4 +/- 2 cycles R from 21 U.S. centers. Pts with PMBCL, PTLD or receiving non-standard dose RCHOP for cycle (C) 1 or planned consolidative RT were excluded. The primary endpoint was PFS from C1 by Kaplan-Meier method, not counting indolent lymphoma relapse. Event free survival (EFS) was time to next therapy without progression (including unplanned RT for non-CR), progression or death. A competing risks analysis of non-relapse mortality (NRM) vs. DLBCL progression was performed. Results: The characteristics of the 428 pts were: median age 60 (18-88), 60% male, 11% Hispanic and 4% non-Hispanic Black, 62% stage I, 15% elevated LDH, 3% ECOG PS>1, 5% tumor bulk >7cm, 9% had B-symptoms and median Charlson Comorbidity Index (CCI) was 4 (2-12). IPI was 0, 1 and 2-3 in 42%, 46% and 12% and stage-modified IPI (smIPI) was 0, 1, 2 and 3-4 in 25%, 48%, 21% and 6% of pts. 66% had nodal (59% head/neck, 11% pelvic, 9% multiple above diaphragm, 7% abdominal) and 46% extranodal sites (37% head/neck, 20% gastric/intestinal, 9% spleen, 8% skin/soft tissue); 6% had transformed/concurrent FL/MZL or grade 3B FL, 33% (138/408) were non-GCB cell of origin (COO), 25% (90/357) double expressor (DEL) and 0.5% (2/379) double-hit. 13% had completely resected disease, 97% staging PET and 47% bone marrow biopsy. Median diagnosis to treatment interval was 30 days (IQR 20-43), 6% had dose reductions after C1, 77% had an interim PET (iPET) after C2 (33%) or C3 (67%), 15% received 2 additional cycles R and 4% CNS prophylaxis. CMR rates by iPET were 83% after C2 and 94% after C3, and 95% by end-of-treatment PET. iPET PMR was more likely if smIPI>2 or bulky disease. Median follow-up time was 2.7 years. There were 32 progression events: 14 occurred at the primary site and 17 at distant sites (1 unknown), and 12 occurred after 2 years. Another 11 pts received unplanned RT after RCHOP4 for non-CR. There were 24 deaths, 12 without prior progression. Cause of death was DLBCL in 7 and non-DLBCL in 17 cases (6 infection, 2 ILD, 2 heart failure, 2 second cancer, 1 seizure, 4 unknown). EFS, PFS and OS rates were 88%, 90% and 96% at 3 years. By univariable Cox regression, Black race, elevated LDH, smIPI>2, DEL, increasing CCI, multiple subdiaphragmatic nodal sites and iPET PMR were associated with worse PFS. Non-significant variables of note included COO, extranodal sites, complete resection, missing bone marrow biopsy, missing iPET and additional cycles R. By multivariable analysis (including age>60, stage, ECOG PS>1, elevated LDH, bulky disease, CCI, B-symptoms and DEL), ECOG PS>1 (HR 3.95 p=0.050), CCI (HR 1.29 p=0.003) and DEL (HR 2.02 p=0.069) were associated with worse PFS. Cumulative incidence of DLBCL progression and NRM were 8% and 2% at 3 years. Competing risk analysis by univariable models found that age>60, ECOG PS>1, smIPI>2, elevated LDH, CCI and bulky disease were associated with NRM, while DEL and B-symptoms were associated with DLBCL progression.Conclusion: Presented is the largest retrospective cohort of LS-DLBCL treated uniformly with RCHOP4 to date. Despite modest follow-up time and lack of an “intention-to-treat“ population, this study shows that abbreviated RCHOP4 leads to excellent outcomes in the real-world, albeit with continuous risk of late relapse. smIPI risk factors were associated with worse PFS, though this may in part be driven by risk of non-lymphoma death. As pts with advanced age, poor performance status or comorbidities may benefit from reduced treatment exposure, RCHOP4 should still be considered for these and other “trial-ineligible” pts, particularly if other high-risk features (iPET PMR, DEL or B-symptoms) are absent.

Background Contact aspiration remains a frontline approach for mechanical thrombectomy (MT) in acute ischemic stroke (AIS). Early evidence correlates catheter size with procedural efficiency and clinical outcomes. Larger‐bore (LB) aspiration catheters may enhance clot ingestion, increase aspiration force, and facilitate faster and more complete recanalization. However, the transition from standard LB catheters (0.068‐0.072″) to super‐large‐bore (SLB, ≥0.080″) devices has raised questions regarding both safety and clinical benefit. Although the use of SLB catheters is increasing, comparative data on their performance versus LB catheters remain limited. This study aims to evaluate the safety and efficacy of SLB compared with LB catheters including data from a large multicenter international registry. Methods We retrospectively analyzed patients with AIS due to LVO treated at 46 international stroke centers between January 2013 and June 2025. Among eligible patients, propensity score matching (PSM) at a 5:1 ratio was used to balance baseline characteristics between those treated with standard LB catheters and those treated with SLB catheters. Safety endpoints included intraprocedural complications, symptomatic intracranial hemorrhage (sICH), distal embolization, and 90‐day mortality. Efficacy endpoints included functional independence at 90 days (modified Rankin Scale [mRS] 0‐2), successful recanalization (TICI ≥2b), first‐pass effect (TICI ≥2b on the first aspiration attempt), and procedural timing to TICI2b. Results A total of 3,100 patients were included (LB n=3,024; SLB n=67). After PSM (LB n=335; SLB n=67), safety outcomes were comparable between groups in terms of intraprocedural complications occurred (p=0.5), sICH (p>0.9), embolization to new territory (p=0.2), and 90‐day mortality (p>0.9). Efficacy outcomes were similarly consistent for functional independence (mRS 0‐2) (p>0.9), successful recanalization (p>0.9), first‐pass effect (p=0.5), and time to TICI ≥2b (27.6 vs. 24.5 minutes; p=0.9). These findings remained consistent in the subgroup with ICA and M1 occlusions, with no significant differences in safety (intraprocedural complications [p=0.4], sICH [p>0.9], embolization to new territory [p=0.6], or 90‐day mortality [p>0.9], nor in efficacy outcomes (functional independence at 90 days [p>0.9], successful recanalization [p=0.9], first‐pass effect [p=0.6], and time to TICI ≥2b [p=0.9]). Conclusion In this large multicenter analysis, the use of SLB aspiration catheters demonstrated comparable safety and efficacy to standard LB catheters for MT in AIS. Despite theoretical advantages in aspiration dynamics, SLB devices did not confer significant procedural or clinical benefit over LB catheters. These findings suggest that while SLB catheters are a feasible alternative, technical and clinical outcomes remain comparable to LB catheters. Further prospective studies are warranted to clarify potential clinical advantages. image

Introduction Problematic alcohol use negatively impacts individuals, families and communities. While perceptions regarding alcohol use are likely vital to mitigating problematic alcohol use at the population level, little is known. Perceptions that demarcate normative versus problematic use may be relevant for interventions in communities with normative alcohol use. Our study explores ethnocentric perceptions of alcohol use in a community where alcohol use is historically integrated into its social fabric. Methods Mixed-methods study design using a culturally curated online survey with closed and open-ended responses assessed perceptions regarding alcohol use. Participants were members of the Kodava community: an affluent ethno-linguistic community in Southern India with an international presence. For Kodavas, alcohol consumption is normative and socially sanctioned. We studied perceptions of alcohol use among family members, including factors influencing its use and the impact of problematic alcohol drinking on immediate and extended family in three domains: health, finances and relationships. Results Of 711 total respondents, a small minority of 11.4% (n=81) stated that at least one immediate family member experienced negative impacts of alcohol use. Among respondents who reported on their extended family (n=639), 52.1% (n=333) endorsed at least one member experienced negative impacts. The integration of quantitative and qualitative data elucidates negative impacts of alcohol use within and at the intersections of health, relationships and finances. Conclusions First study to employ social media (WhatsApp) to survey a globally dispersed ethnic community on alcohol use impacts among family members. Interventions tailored to these perceptions, in culturally embedded communities, may improve outcomes. The framework and approach of this study can be replicated globally.