Citations

Background: Left ventricular (LV) injury is a cardioembolic etiology of ischemic stroke. We aimed to 1) evaluate recurrent stroke risk among patients with cryptogenic stroke and LV injury, and 2) determine if there is a treatment effect with anticoagulation in this population. Methods: We analyzed the multicenter, retrospective Cardiac Abnormalities in Stroke Prevention and Recurrence cohort of patients with cryptogenic ischemic stroke. The exposure was LV injury defined by 1) LV ejection fraction (EF) 20-40% and/or 2) LV wall motion abnormality (hypokinesis or akinesis). The primary composite outcome included recurrent stroke, major bleeding, or death. Cox proportional hazard models were built and sequentially adjusted for 1) age and sex (Model 1), and 2) age, sex, race, ethnicity, anti-thrombotic use, and vascular risk factors (Model 2). We then assessed if there was heterogeneity in treatment effect by LV injury status with an interaction term of LV injury and oral anticoagulation use in Model 2. Results: Of 2,641 patients in CASPR, the analytic cohort included 2,191 patients with complete exposure and outcome data (median age 65 years, 49.8% female, median follow-up 1.55 years). There were 113 (5.2%) patients with LV injury (median LVEF 30%, interquartile range 25-34%). There were 559 incident events (321 recurrent strokes [288 ischemic], 71 major hemorrhages, 250 deaths). Among patients with LV injury, 15.9% were prescribed an anticoagulant within 7 days of index stroke (vs 9.6% without LV injury, p=0.03). The unadjusted risk of the primary outcome was non-significantly higher among patients with LV injury vs without (HR 1.40; 95% confidence interval [CI], 0.98-2.00), but became significant in Model 1 (HR 1.50; 95% CI, 1.21-1.85) and in Model 2 (HR 1.35, 95% CI, 1.11-1.64). In the LV injury subgroup, anticoagulation vs antiplatelet therapy was associated with a significant reduction in the primary outcome (HR 0.63, 95% CI, 0.43-0.94). In patients without LV injury, anticoagulation was associated with a higher risk of the composite outcome (HR 4.35, 95% CI, 1.69-11.16, p[interaction]=0.002). Conclusion: In this observational study, there was an increased risk of the primary outcome which included recurrent stroke among patients with cryptogenic stroke and LV injury. Anticoagulation use in LV injury is associated with a significant reduction in the risk of the primary outcome. These findings warrant confirmation in a dedicated randomized controlled trial.

AbstractDefining the CSF cytokine/chemokine and injury biomarker signature of glial fibrillary acidic protein (GFAP) autoimmunity can inform immunopathogenesis. CSF GFAP‐IgG‐positive samples (N = 98) were tested for 17 cytokines/chemokines, neurofilament light chain (NfL), and GFAP (ELLA, Bio‐Techne). Controls included non‐inflammatory (N = 42), AQP4‐IgG‐positive (N = 83), CNS infections (N = 13), and neurosarcoidosis (N = 32). IL5, IL6, IL10, IL8/CXCL8, CXCL9, CXCL10, CXCL13, BAFF, GM‐CSF, IFN‐gamma, and TNF‐alpha concentrations were higher compared to non‐inflammatory controls (P < 0.01). GFAP concentrations were similar to those of AQP4‐IgG‐positive patients; NfL was higher (P < 0.001) and correlated with MRI changes and outcomes. CSF cytokine/chemokine findings in GFAP autoimmunity correlate with histopathology; GFAP and NfL hold promise as disease biomarkers.

270 Background: While immune checkpoint blockade (ICB) is used to treat metastatic deficient mismatch repair (dMMR) colorectal cancers (CRCs), such tumors are heterogeneous and resistance to ICB is frequent. To date, biomarkers that can consistently predict patient response to ICB are lacking. We determined whether biomarkers that integrate tumor and immune-related molecular mechanisms could predict ICB response. Methods: Consecutive patients with metastatic dMMR CRCs (N=32) who had been treated with anti-PD-1 therapy were profiled using a validated immune-enhanced exome and transcriptome platform (ImmunoID NeXT, Personalis) using tumor and paired normal tissue. This platform provides antigen-specificity of T or B cells, indicated by the TCR or BCR respectively, neoantigen prediction, tumor mutation burden (TMB), immune profile, HLA allele-specific loss of heterogeneity (LOH) and a Neoantigen Presentation Score (NEOPS) that combines a neoantigen prediction tool with mechanisms of immune evasion. Tumor variables were analyzed in relationship to objective tumor response, and a Cox proportional hazards model was fit to predict progression-free survival (PFS) or overall survival (OS). Results: In CRCs, TCR and BCR repertoire diversity were each significantly increased in tumors from responders versus those with stable or progressive disease after anti-PD-1 treatment (p=0.015 and p=0.048, respectively). Neoantigen burden score, TMB, and HLA allele-specific LOH (reflects loss of antigen presentation machinery) were each unable to distinguish responders from nonresponders. An immune checkpoint gene expression signature was increased in nonresponders relative to responders (P= 0.005). Neoantigen presentation score (NEOPS) was prognostic when adjusted for tumor grade only for OS (p=0.048). Conclusions: The T-cell and B-cell receptor (TCR/BCR) repertoire, as well as NEOPS, were each significantly predictive of favorable response to anti-PD-1 therapy in dMMR tumors. In addition, an immune checkpoint gene expression signature was predictive of resistance to ICB.

Background: Anterior cruciate ligament reconstruction (ACLR) is one of the most common orthopaedic procedures and one of the most well studied. Despite extensive research dedicated to ACLR, there is limited understanding of how chronic inflammatory systemic diseases (CIDs) such as rheumatoid arthritis and systemic lupus erythematosus affect outcomes. Purpose: To compare the outcomes of ACLR in cohorts of patients with and without CID. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective query of a regional data set was conducted for all patients who underwent ACLR from 1990 to 2021 for traumatic ACL rupture. All patients with CID were identified and propensity matched to non-CID controls. Baseline characteristics and clinical outcomes were identified through retrospective chart review, and patients were contacted for subjective outcomes. Results: A total of 30 patients with ACLR and a diagnosis of CID were identified. These patients were propensity matched to 120 non-CID controls. Baseline demographic and surgical characteristics demonstrated no statistical differences. Follow-up duration was similar between the CID and non-CID groups (mean, 14.6 vs 14.2 years; P = .868). The CID cohort had a higher arthrofibrosis rate (16.7% vs 4.3%; P = .031), higher osteoarthritis rate (33.3% vs 16.7%; P = .041), higher total knee arthroplasty (TKA) rate (16.7% vs 3.3%; P = .016), and earlier time to TKA (14.7 vs 23.5 years; P = .032). Knee range of motion, infection rate, retear rate, time to retear, and time to osteoarthritis were not statistically different between the cohorts. The CID cohort had higher visual analog scale pain scores (mean, 2.00 vs 1.20; P = .043) but slightly higher satisfaction (mean, 3.92 vs 3.39; P = .043). There were no differences in preinjury Tegner, postoperative Tegner, change in Tegner, or IKDC score. In a univariate Cox regression model, the CID cohort had a retear hazard ratio of 1.43 (95% CI, 0.46-4.51; P = .537). Kaplan-Meier survival revealed no significant differences in retear-free survival between the CID and non-CID cohorts at 25 years (85.7% vs 87.3%; P = .53). The CID cohort had a TKA hazard ratio of 3.94 (95% CI, 1.05-14.8; P = .042). Kaplan-Meier survival demonstrated significantly decreased TKA-free survival at 25 years in the CID cohort (64.9% vs 91.2%; P = .029). Conclusion: CID increases the incidence of arthrofibrosis, osteoarthritis, and TKA in those undergoing ACLR. Patients with CID also undergo TKA significantly sooner than non-CID counterparts. Notably, the majority of patient-reported outcome measures are no worse in patients who have a CID diagnosis. Thus, ACLR constructs themselves may not necessarily fare worse in patients with CID. Nonetheless, these patients need to be cautiously counseled on the clinical outlook after their ACLR.

Introduction Optimal hospital bed utilization requires innovative patient care models. We studied a novel hospitalist model utilizing telemedicine to facilitate collaboration with affiliated emergency departments (EDs) and support medical triage and care of ED patients with high likelihood of hospital admission. Methods Telehospitalists based at a tertiary care facility collaborated with four community EDs in the same healthcare network between January 1, 2022, and April 30, 2023. Telehospitalists supported ED clinicians in medical care decisions and facilitated patient disposition. Emergency department length of stay (LOS) and disposition were evaluated, as were hospital LOS, 30-day readmission, and in-hospital mortality. For patients discharged from the ED, 7-day ED readmission and subsequent hospitalization were evaluated. Results Telehospitalists discussed 550 “admit-likely” patients with ED clinicians: 105 patients (19.1%) discharged from the ED and avoided admission; 322 patients (58.5%) were admitted to local or nearby community hospitals; 123 patients (22.4%) transferred to the tertiary care facility. Emergency department LOS differed significantly among disposition groups, including patients discharged home (10.2 h), admitted to local hospitals (12.6 h), and transferred to tertiary care hospitalist services (14.9 h; p < 0.001). Hospital LOS and in-hospital mortality were not significantly different among disposition groups. Patients admitted locally had lower 30-day readmission compared to those transferred to tertiary care facility (odds ratio = 0.59 [0.36, 0.99], p = 0.048). Discussion Telehospitalists as triage clinicians is an innovative approach to support local ED clinicians and patients. Telehospitalists optimized hospital bed utilization and healthcare system resources by facilitating safe discharges to home and expediting tertiary care transfers when necessary.

Background Data regarding long-term recovery from autoimmune encephalitis (AE) remain limited. Methods This retrospective observational study investigated outcomes in 182 patients who met the 2016 criteria for definite AE. Recovery data were available in 172 patients. Follow-up data at ≥24 months post-attack were available for 119. Recovery trajectory, residual symptoms, outcome predictors and causes of post-AE death were assessed. Results Of 172 patients, 138 (80%) achieved good recovery (modified Rankin Scale (mRS) ≤2) with a median recovery time of 4 months (95% CI: 2 to 6 months). Recovery varied by associated neural antibody, with the best recovery observed in leucine-rich glioma-inactivated 1 (97% good recovery, median recovery time 0 (0 to 2) months). Paraneoplastic AE (p=0.007), severe attacks (eg, mRS ≥4 at attack, p=0.007) and cerebrospinal fluid pleocytosis (p=0.005) were associated with a lower likelihood of good recovery, while seizure presentation (p=0.026) was associated with better recovery. Despite good recovery, several residual symptoms persisted ≥24 months post-AE, including cognitive deficits (53%), seizures (26%), depression (23%), sleep disorders (25%), brainstem/cerebellar symptoms (13%), other movement disorders (14%) and autonomic symptoms (12%). Predictors of long-term sequelae included disabling cognitive deficit at onset and delayed immunotherapy for post AE-dementia, and medial temporal atrophy as well as escalation to cyclophosphamide therapy for both drug-resistant epilepsy and chronic depression. Of 182 patients, 20 (11%) died; the most common cause of death was progression of AE (6/20 (30%)). Conclusion While the majority of patients achieved functional independence after AE, several residual symptoms persisted. Several clinical and paraclinical features were associated with long-term sequelae.

Abstract Purpose: Two randomized clinical trials (STOMP and ORIOLE) demonstrated that stereotactic ablative radiotherapy (SABR) can prolong androgen-deprivation therapy–free survival or progression-free survival (PFS) in patients with metachronous oligometastatic castration-sensitive prostate cancer (omCSPC). Although most patients with omCSPC have a more modest delay in progression, a small subset achieves a durable response following SABR. We investigated the prognostic and predictive value of circulating prostate-specific membrane antigen-positive (PSMA+) extracellular vesicles (EV) and PSA in a biomarker correlative study using blood samples from three independent patient cohorts. Experimental Design: Plasma samples from 46 patients with omCSPC on the ORIOLE trial and 127 patients with omCSPC on the STOMP trial protocol treated with SABR were included in the study. Pre-SABR PSMA+EV levels (EV/mL) were measured by nanoscale flow cytometry. Kaplan–Meier curves and logistic regression models were used to determine the association of PSMA+EV and PSA levels with clinical outcomes. Results: In the pooled cohorts, the median biochemical PFS were 26.1 and 15.0 months (P = 0.005), and the median radiographic PFS were 36.0 and 25.0 months (P = 0.003) for PSMA+EV-low and -high groups, respectively. The combination of pre-SABR low levels of both PSMA+EV and PSA was associated with a lower risk of radiographic progression (HR, 0.34, 95% confidence interval, 0.18–0.58; P = 0.0002). In the ORIOLE cohort, which included both an SABR arm and an observation arm, low PSMA+EV was predictive of benefit from SABR (P = 0.012). Conclusions: PSMA+EV is a novel prognostic and predictive biomarker of radiographically occult tumor burden in omCSPC. PSMA+EV may inform clinical decisions about identifying patients who will achieve a durable benefit from consolidative SABR alone.

Background: The incidence and mortality of anal squamous cell carcinoma (ASCC) are rising, with greater than 80% of cases linked to human papillomavirus (HPV), primarily HPV16. Post-treatment surveillance can be challenging due to the limitations of anoscopy, digital anal rectal exam (DARE), and imaging. Plasma tumor tissue modified viral (TTMV)-HPV DNA has shown strong sensitivity, specificity, and predictive value in detecting the recurrence of HPV-driven oropharyngeal cancer. Here, we investigate the ability of TTMV-HPV DNA for the early recurrence detection of ASCC. Methods: This retrospective clinical case series included 117 patients with HPV-driven ASCC across 7 U.S. centers, monitored with TTMV-HPV DNA during routine clinical care between March 2020 and June 2024. Physician-reported clinical data and biomarker testing data were combined to create a comprehensive, longitudinal dataset for evaluating test performance metrics. Results: Patients had a median age of 63 years and median post-diagnosis follow-up of 19 months. HPV status was primarily confirmed by TTMV-HPV DNA (52%) or p16 immunohistochemistry (39%). Of those tested for TTMV-HPV DNA pretreatment, 85% had a positive result. TTMV-HPV DNA clearance during or within three months post-treatment was associated with significantly better recurrence-free survival. The per-patient surveillance sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 82.8%, 98.4%, 96.0%, and 92.5%. Of 24 patients with a documented recurrence and a positive TTMV-HPV DNA test, the test was the first evidence of recurrence in 14 patients (58.3%), with a median lead time of 59 days (range: 10–536). TTMV-HPV DNA accurately resolved 94.3% of cases with indeterminate clinical findings. Conclusions: TTMV-HPV DNA testing provides a sensitive and specific approach for detecting patients with recurrent ASCC and resolving the status of patients with indeterminate clinical findings.

ABSTRACTPurposeDouble‐level osteotomies (DLOs) have shown promising results for knee joint preservation, however, most ultimately progress in terms of degenerative disease resulting in conversion to total knee arthroplasty (TKA). Therefore, the purpose of this study was to examine the time to TKA conversion, long‐term clinical outcomes and revision rates of patients who have undergone TKA after prior ipsilateral DLO.MethodsPatients who underwent simultaneous or staged DLO and subsequently underwent conversion to TKA at a single academic institution from 1997 to 2022 were evaluated. The type of osteotomy performed (opening‐ vs. closing‐wedge), osteotomy hardware fixation, when and if osteotomy hardware was removed, implanted TKA components and revision rates were recorded. Postoperative outcomes, including Forgotten Joint Score‐12 (FJS‐12), Tegner Activity Scale score and subjective knee preference were also obtained.ResultsA total of 22 patients (24 knees) underwent TKA following DLO and were followed for an average of 26.1 ± 7.7 years. The average time from DLO to TKA conversion was 14.1 ± 6.5 years, with 70.8% of knees converting to TKA more than 10 years after DLO. The mean follow‐up after conversion to TKA was 12.0 ± 7.7 years. Only 12.5% of patients received a varus‐valgus or hinged‐constrained TKA. At the final follow‐up, the mean FJS‐12 was 75.8 ± 23.1, while the mean Tegner Activity Scale score was 2.5 ± 1.1. Seventy‐seven percent of patients had no subjective knee preference or preferred their DLO‐TKA knee. Only two knees (7.4%) underwent subsequent revision after index arthroplasty at a mean of 9.3 years postoperatively.ConclusionsA majority of DLOs (70.8%) converted to TKA after more than a decade. Subsequent TKA function was favorable as most patients had either no subjective knee preference or preferred their DLO‐TKA knee. This study demonstrates both long‐term joint preservation and uncompromised TKA function after prior DLO.Level of EvidenceLevel IV.