Citations

Abstract Delivery of therapeutics to solid tumors with high bioavailability remains a challenge and is likely the main contributor to the ineffectiveness of immunotherapy and chemotherapy. Here, a catheter‐directed ionic liquid embolic (ILE) is bioengineered to achieve durable vascular embolization, uniform tissue ablation, and drug delivery in non‐survival and survival porcine models of embolization, outperforming the clinically used embolic agents. To simulate the clinical scenario, rabbit VX2 orthotopic liver tumors are treated showing successful trans‐arterial delivery of Nivolumab and effective tumor ablation. Furthermore, similar results are also observed in human ex vivo tumor tissue as well as significant susceptibility of highly resistant patient‐derived bacteria is seen to ILE, suggesting that ILE can prevent abscess formation in embolized tissue. ILE represents a new class of liquid embolic agents that can treat tumors, improve the delivery of therapeutics, prevent infectious complications, and potentially increase chemo‐ and immunotherapy response in solid tumors.

Objective: To assess whether diffusion restriction (DR) of the retina and optic nerve (ON) can be accurately and reliably identified on standard stroke protocol brain magnetic resonance diffusion-weighted imaging (DWI-MRI) in patients presenting with acute non-arteritic central retinal artery occlusion (CRAO). Background: Retinal DR (RDR) and ONDR in patients with acute non-arteritic CRAO have been described with various diagnostic accuracies and often identified by experienced neuroradiologists with fair inter-rater agreement. Methods: This retrospective case-control study included patients that presented to our academic center from 2013-2021 with acute non-arteritic CRAO or acute cerebral ischemia (controls, age and gender-matched) and had brain MRI performed within 14 days from symptom onset. Two neuroradiologists, blinded to the site of CRAO and diagnosis, independently reviewed MRI of CRAO cases and controls to assess for the presence of RDR and ONDR. Their inter-rater agreement was calculated (prevalence and bias- adjusted kappa coefficient) and their final consensus was used to perform sensitivity and specificity analyses. Results: We included 128 patients with CRAO (mean age 69 years; 50% males; median time from CRAO to MRI 2 days (IQR 1-5)) and 128 matched controls with acute cerebral ischemia (mean age 68 years; 51% males). After neuroradiologists’ consensus, DR was correctly identified in the retina or ON in 51/128 (39.8%), retina alone 35/128 (27.3%), ON alone 31/128 (24.2%), both retina and ON 15/128 (11.7%), with excellent inter-rater agreement for retina (K=0.91) and ON (K=0.83). There were no cases of RDR or ONDR in the control group. After neuroradiologists’ consensus, sensitivity, specificity, PPV and NPV were 28.1%, 100%, 100%, and 58.2% for RDR and 27.3%, 100%, 100%, and 57.9% for ONDR. Conclusion: Though RDR and ONDR can be identified with excellent interrater reliability, they are infrequent findings and their role in diagnosing acute CRAO is unclear. Observational prospective studies with large cohort of patients, optimization of dedicated and standardized orbit DWI-MRI protocols, and education of neurology and neuroradiology providers are needed to facilitate more accurate identification of RDR and ONDR in hyperacute CRAO.

Introduction: Recent studies report similar outcomes with antiplatelet drugs and intravenous thrombolysis (IVT) in patients with minor nondisabling ischemic stroke. These patients still meet emergent triage criteria and can increase the burden on stroke systems through prehospital stroke activation. Prehospital large vessel occlusion (LVO) scales can improve triage of LVO patients but have not been evaluated as tools to predict IVT administration. We sought to determine if common LVO scales can predict IVT use in a large academic telestroke practice. Methods: This retrospective study included all video telestroke consults performed in a large academic telestroke network from 2019-2020. Patients were excluded if they were on anticoagulation, presented beyond 4.5 hours from last known well, or family declined IVT due to goals of care. We recorded presenting NIHSS and IVT recommendations. NIHSS was used to calculate 7 LVO scales (RACE, G-FAST, FAST-ED, VAN, PASS, 3I-SS, and C-STAT). Scale performance was assessed by calculating area under curve (AUC) and compared to NIHSS total score using the DeLong test. Youden cutpoint was established for each scale and subsequently used to calculate sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy. Results: A total of 513 patients were included; 205/513 (40%) were recommended IVT. Median (IQR) NIHSS was 1 (0-3) in non-IVT patients and 6 (4-11) in IVT patients. The RACE and G-FAST scales were noninferior to the NIHSS in predicting IVT recommendation (Table 1). Conclusion: The RACE and G-FAST scales may be useful triage tools to identify patients needing emergent stroke evaluation for consideration of IVT.

Introduction: Telestroke enables timely and remote evaluation of patients with acute stroke syndromes. However, stroke mimics represent more than 30% of this population. Given the resources required for management of suspected acute ischemic stroke, several scales have been developed to help identify stroke mimics. Our objective was to externally validate four mimic scales (Khan Score [KS], TeleStroke Mimic Score [TS], simplified FABS [sFABS], and FABS) in a large, academic telestroke network. Methods: This is a retrospective, IRB exempt study of all patients who presented with suspected acute stroke syndromes and underwent video evaluation between 2019-2020 at a large academic telestroke network. Detailed chart review was conducted to extract both the variables needed to apply the mimic scales the final diagnosis confirmed by final imaging and discharge diagnosis (cerebral ischemic vs stroke mimic). Overall score performance was assessed by calculating area under curve (AUC). Youden cutpoint was established for each scale and used to calculate sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy. Results: A total of 1043 patients were included in the final analysis. Final diagnosis of cerebral ischemia was made in 662/1043 patients (63.5%) and stroke mimic was diagnosed in 381/1043 patients (36.5%). To predict stroke mimic, TS had the highest AUC (68.3) and PPV (73%); KS had the highest accuracy (68.6%), sensitivity (86.6%) and NPV (61.5%); and FABS had the highest specificity (54.8%) (Table 1). Conclusions: While each scale offers unique strengths, none was able to identify stroke mimics effectively enough to confidently apply in clinical practice. There remains need for significant clinical judgment to determine the likelihood of stroke mimic at presentation.

Background The rapid evolution of artificial intelligence (AI) in conjunction with recent updates in dual antiplatelet therapy (DAPT) management guidelines emphasizes the necessity for innovative models to predict ischemic or bleeding events after drug‐eluting stent implantation. Leveraging AI for dynamic prediction has the potential to revolutionize risk stratification and provide personalized decision support for DAPT management. Methods and Results We developed and validated a new AI‐based pipeline using retrospective data of drug‐eluting stent‐treated patients, sourced from the Cerner Health Facts data set (n=98 236) and Optum's de‐identified Clinformatics Data Mart Database (n=9978). The 36 months following drug‐eluting stent implantation were designated as our primary forecasting interval, further segmented into 6 sequential prediction windows. We evaluated 5 distinct AI algorithms for their precision in predicting ischemic and bleeding risks. Model discriminative accuracy was assessed using the area under the receiver operating characteristic curve, among other metrics. The weighted light gradient boosting machine stood out as the preeminent model, thus earning its place as our AI‐DAPT model. The AI‐DAPT demonstrated peak accuracy in the 30 to 36 months window, charting an area under the receiver operating characteristic curve of 90% [95% CI, 88%–92%] for ischemia and 84% [95% CI, 82%–87%] for bleeding predictions. Conclusions Our AI‐DAPT excels in formulating iterative, refined dynamic predictions by assimilating ongoing updates from patients' clinical profiles, holding value as a novel smart clinical tool to facilitate optimal DAPT duration management with high accuracy and adaptability.

Staphylococcus aureus skin colonization and eosinophil infiltration are associated with many inflammatory skin disorders, including atopic dermatitis, bullous pemphigoid, Netherton’s syndrome, and prurigo nodularis. However, whether there is a relationship between S. aureus and eosinophils and how this interaction influences skin inflammation is largely undefined. We show in a preclinical mouse model that S. aureus epicutaneous exposure induced eosinophil-recruiting chemokines and eosinophil infiltration into the skin. Remarkably, we found that eosinophils had a comparable contribution to the skin inflammation as T cells, in a manner dependent on eosinophil-derived IL-17A and IL-17F production. Importantly, IL-36R signaling induced CCL7-mediated eosinophil recruitment to the inflamed skin. Last, S. aureus proteases induced IL-36α expression in keratinocytes, which promoted infiltration of IL-17-producing eosinophils. Collectively, we uncovered a mechanism for S. aureus proteases to trigger eosinophil-mediated skin inflammation, which has implications in the pathogenesis of inflammatory skin diseases.

Background: Cellular senescence has been associated with neurodegenerative disease and clearance of senescent cells using genetic or pharmaceutical strategies (senolytics) has demonstrated beneficial effects in mouse models investigating individual disease etiologies of Alzheimer’s disease (AD). However, it has remained unclear if senescent cell clearance in a mouse model exhibiting both plaque and tau pathologies modifies the disease state (3xTg). Objective: To investigate the effects of senescent cell clearance in the 3xTg mouse model. Methods: 3xTg mice were treated with senolytics (ABT263 (navitoclax; NAVI), a combination of dasatinib and quercetin (D+Q)), or subjected to transgene-mediated removal of p16-expressing cells (via INK-ATTAC). Results: Senolytic treatments consistently reduced microgliosis and ameliorated both amyloid and tau pathology in 3xTg mice. Using RNA sequencing, we found evidence that synaptic dysfunction and neuroinflammation were attenuated with treatment. These beneficial effects were not observed with short-term senolytic treatment in mice with more advanced disease. Conclusions: Overall, our results further corroborate the beneficial effects senescent cell clearance could have on AD and highlight the importance of early intervention for the treatment of this debilitating disease.

458 Background: Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 axis has revolutionized the therapeutic landscape of patients with advanced and locally advanced renal cell carcinoma (RCC). However, complete response rates remain low and there is a need for novel therapeutic options for ICI-resistant and refractory RCC. Our group has generated a novel humanized anti-PD-L1 antibody, called H1A, that induces PD-L1 degradation preventing not only its interaction with PD-1 but also inhibiting pro-tumorigenic intracellular signaling. In this study, we compared the antitumor activity of H1A with FDA-approved ICI using patient-derived immune cells and humanized mouse tumor models. Methods: In vivo antitumor activity of H1A and atezolizumab (ATZ) was compared in three humanized PD-1/PD-L1 mouse tumor models with different immunogenicity (E0771:high, MC38:moderate, B16-F10:poor). Peripheral blood mononuclear cells (PBMC) were isolated from 14 RCC patients undergoing with nephrectomy. PBMC were treated with H1A, nivolumab (NIV), atezolizumab (ATZ) and pembrolizumab (PEM) to evaluate their efficacy in inducing tumor cell death in an ex-vivo cytotoxicity assay. Mass cytometry was employed to determine the impact of H1A and atezolizumab on the PBMC profile. Results: MC38 tumors showed moderate response to both H1A and ATZ which was abrogated by CD8 T cell depletion. In E0771 tumors, higher percentage of complete responders was observed with H1A compared to ATZ and E0771 rechallenge revealed memory antitumor immunity with complete rejection of tumors. Patient-derived PBMC treated with H1A showed superior tumor cell killing compared to NIV, PEM and ATZ (p<0.01). While H1A treatment of PBMC induced expansion of effector NK and CD8 T cells (GZMB+ T-bet+), ATZ treatment led to enrichment of Tregs (CD25+,Foxp3+) expressing inhibitory markers PD-1 and LAG-3. Conclusions: H1A demonstrated superior antitumor activity compared to FDA-approved ICI which lays the ground for clinical testing of H1A as a next-generation immune checkpoint inhibitor for the treatment of renal cell carcinoma.

385 Background: Tyrosine kinase inhibitors (TKI) and immuno-oncology (IO) agents alone or in combination have revolutionized the landscape of management for untreated metastatic renal cell carcinoma (mRCC). Baseline quality of life (QOL) outside of interventional clinical trials and rationale for management decisions in mRCC are poorly understood. Methods: In this prospective observational study of 800 mRCC pts in the US, pts must: have a diagnosis of mRCC (any histology) with no prior systemic therapy (ST) for mRCC; be age ≥19 at informed consent; be able to comply with completion of PROs. Exclusion criteria include being treated for active malignancy other than mRCC or not intending to follow up at a study site within PCORnet. Pts undergo consent and baseline assessments by the study site team, with subsequent follow up by the central coordinating center. The primary objective is to determine distinct patterns of change in QOL and symptom burden of mRCC pts. A key secondary objective is to identify patterns of clinical management in the real world setting of mRCC across treatment regimens. Minimally important differences are defined as 3- and 7-points for FKSI-19 and FACT-G respectively. ClinicalTrials.gov ID: NCT04919122. Results: As of 9/1/2023, 173 pts have been enrolled (126 ST, 47 no ST [NST]): 75% male, 87% white, 73% clear cell, 52% intermediate risk and 47% poor risk. 47% had radical nephrectomy and 22% another solid tumor. ST pts as compared to NST pts were more likely to be poor risk (52% vs 16%); but differences in baseline pain were not significant. Of ST pts, 44 were treated with IO-IO (ipilimumab + nivolumab), 50 with IO-TKI (cabozantinib + nivolumab 38%, axitinib + pembrolizumab 38%, lenvatinib + pembrolizumab 24%) and 32 other (IO alone 34%, TKI alone 31%, investigational drug 25%). Reasons for NST included active surveillance (AS, 50%), other (21%), local therapy (13%). Mean differences between ST and NST for baseline FKSI-19 and FACT-G were 5.7 (95% CI: 1.2 – 10.2) and 3.3 (-2.6 – 9.3). There were no differences in pain or PROs between IO-IO and IO-TKI pts. Mean differences in FKSI-19 and FACT-G between AS vs IO-IO were 10.6 (4.8 – 16.4) and 8.6 (1.1 – 16.0); and vs IO-TKI were 11.0 (4.9 – 17.0) and 10.3 (3.5 – 17.1). On physician surveys, primary reasons for treatment selection were (in order of % selected): complete response (CR), prolonged survival (OS), prognostic factors (Px), treatment-free interval for IO-IO; versus delaying progression (PFS), OS, CR, Px for IO-TKI. Conclusions: Our data suggest differences in baseline QoL in pts treated with ST vs NST, as well as AS vs IO-IO or IO-TKI, in the real world. Reasons for selection of ST regimen differed among combination regimen classes. Completion of ODYSSEY will clarify baseline and longitudinal differences in pain and PROs among management strategies and give novel insights into the rationale for real world management of untreated pts with mRCC. Clinical trial information: NCT04919122 .

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43–depleted human iPSC–derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43–depleted human iPSC–derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43–depleted human iPSC–derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.