Citations

Background Studies during the COVID-19 pandemic have demonstrated an association between COVID-19 virus infection and the development of acute ischemic stroke, particularly large vessel occlusion (LVO). Studying the characteristics and immunohistochemistry of retrieved stroke emboli during mechanical thrombectomy for LVO may offer insights into the pathogenesis of LVO in COVID-19 patients. We examined retrieved COVID-19 emboli from the STRIP, EXCELLENT, and RESTORE registries and compared their characteristics to a control group. Methods We identified COVID-positive LVO patients from the STRIP, RESTORE, and EXCELLENT studies who underwent mechanical thrombectomy. These patients were matched to a control group controlling for stroke etiology based on Trial of Org 10172 in Acute Stroke Treatment criteria. All clots were stained with Martius Scarlet Blue (MSB) along with immunohistochemistry for interleukin-6 (IL-6), C-reactive protein (CRP), von Willebrand factor (vWF), CD66b, fibrinogen, and citrullinated Histone H3. Clot composition was compared between groups. Results Nineteen COVID-19-positive patients and 38 controls were included. COVID-19-positive patients had a significantly higher percentage of CRP and vWF. There was no difference in IL-6, fibrin, CD66b, or citrullinated Histone H3 between groups. Based on MSB staining, there was no statistically significant difference regarding the percentage of red blood cells, white blood cells, fibrin, and platelets. Conclusions Our study found higher concentrations of CRP and vWF in retrieved clots of COVID-19-positive stroke patients compared to COVID-19-negative controls. These findings support the potential role of systemic inflammation as indicated by elevated CRP and endothelial injury as indicated by elevated vWF as precipitating factors in thrombus development in these patients.

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

136 Background: Studies using International Classification of Diseases (ICD) codes have aimed to characterize the safety profile of cancer therapies in the Real-World Data setting, but this approach has limitations including an inability to illustrate patient journey and offer insights into drug-Adverse Event (AE) causality. Using data from a cohort of ~9000 patients treated with immune checkpoint inhibitors (ICI) at Mayo Clinic, we recently demonstrated the feasibility of applying Augmented Curation (AC), a natural language processing (NLP)-based innovation, on unstructured electronic health record (EHR) data to detect and characterize immune related AEs (irAEs). While the ability to identify and extract clinical details from EHRs has been previously demonstrated, our approach focuses on applying these techniques to identify implied textual causality of drug-event pairs. This study aims to build upon our prior findings and compare the accuracy, speed, and resource savings enabled by AC analysis versus manual review of patient notes. Methods: We compared the prevalence of adrenal insufficiency, colitis, and hypophysitis (A.C.H) among ICI patients at Mayo Clinic using ICD codes and AC which leverages SciBERT to perform scientific NLP tasks. AC models trained to identify drug-adverse event relationships were used to assess irAEs and subsequent treatments and demonstrated strong performance with F1 scores of 0.85. Manual curation of relevant clinical data, i.e. medications and adverse events, was employed to create a “gold standard” A.C.H. cohort. Time required for manual review compared to AC was documented for overall comparison. Corticosteroid/immunosuppressant use and ICI discontinuations were used as proxies of severity. Results: In our cohort, 540 unique patients experienced at least one of the A.C.H. irAEs. A.C.H patients were found to receive corticosteroids for their respective irAE 79% of the time and discontinued the ICI due to the irAE 7.7% of the time. 6.1% of Colitis patients were treated with a 2L immunosuppressant. Similar to the previous study, AC showed higher sensitivity, PPV and NPV compared to ICD codes alone within the A.C.H. cohort. Sentence extraction and entity classification using AC models on all 9,000-patients took ~10 minutes, whereas manual review of this cohort would take roughly 9 weeks (~10 minutes per patient). Conclusions: The results from this study reinforce that AC models are a valuable tool to comprehensively extract information and to impute relationships between entities, such as therapies and AEs. The AC models demonstrated better accuracy at a much greater speed compared to manual review of patient EHRs. Leveraging AC models provides the ability to manipulate unstructured clinical text married to structured EHR data at scale while minimizing need for manual curation.

Introduction EXCELLENT (NCT03685578; Cerenovus) is a large, prospective, international, real‐world registry of endovascular clot removal in acute ischemic stroke (AIS) with EmboTrap as the first line mechanical thrombectomy (MT) device, which included collection and analysis of the retrieved thrombus material. Methods Between September 2018 and March 2021, 1000 “all‐comer” patients were enrolled at 34 global sites (27 US, 5 EU, 1 UK, 1 Israel) and treated according to standard of care at each center (with Embrotrap as first line). The study employed blind endpoint evaluation, including a core imaging lab and an independent 90‐day mRS assessment. Retrieved clot was collected per each MT maneuver from 538 subjects across 26 sites and clot analysis was performed by independent central labs blinded to clinical data. Results mITT population included 998 subjects. Mean age was 69.9±14.18 years (range 18–102), 51.8% (517/998) subjects were female and 9.9% (97/997) had a pre‐stroke mRS 3–5. Baseline NIHSS was 15.6±6.87 (range 0–36); 10.1% (82/815) subjects had a large core (ASPECTS 0–5); 5.8% (57/990) had posterior stroke; 56.3% (523/929) underwent MT ≤ 6hrs of onset and 38.1% (380/998) received IV‐tPA prior to MT. First pass eTICI 2c‐3 was achieved in 38.3% (377/984) and final 2b‐3 in 94.5 % (930/984; median number of passes = 1) of subjects. 90‐day mRS≤2 or ≤pre‐stroke was 46.9% (429/915) and 90‐day all‐cause mortality was 19.0% (175/921). The univariate analysis of clot components showed high red blood cell and low platelet content were significant predictors of good mRS outcome (p < 0.001 and 0.009) and negative predictors of 90‐day mortality (p < 0.001 and 0.017, respectively). Conclusions This large multi‐center, all‐comer cohort reflects the population undergoing thrombectomy today in a real world‐setting. Final angiographic, clinical and thrombus composition results, along with multivariate analysis of predictors of clinical outcomes, will be presented at the time of the conference.

Abstract Chemotherapy-induced cognitive impairment (CICI, also termed “chemobrain”) is a major neurotoxic side effect exhibited by a wide range of chemotherapeutic agents. These side effects affect approximately 14 million cancer survivors. More importantly, CICI persists well after cessation of therapy, severely interfering with quality of life. Unfortunately, there is no treatment and novel therapies are urgently needed. Utilizing cisplatin, a platinum-based chemotherapy, to model chemobrain mice in vivo, we have established that cisplatin accelerates the brain aging process thus leading to long-term memory impairment in mice similar to what is clinically reported. We further show that cisplatin causes oxidative DNA damage, mitochondrial defects, impaired neurogenesis, synaptic defects, and increased gliosis in the adult hippocampus, a brain region critical for learning and memory. Mechanistically, our RNA-sequencing and qRT-PCR analysis revealed that cisplatin dramatically increases COX-2 (Ptgs2) expression and its major product, prostaglandin E2 (PGE2) in adult mouse brain and human cortical neurons derived from induced pluripotent stem cells (iPSCs). Similar as cisplatin treatment, the levels of COX-2 expression began to increase at 0.1 µM methotrexate treatment, which significantly increased at 1 µM in human cortical neurons, indicating that COX-2 induction is a common pathogenic mechanism mediating cognitive impairment associated with cisplatin and methotrexate in spite of the fact that these compounds have different mechanisms of action for cancer eradication. Most importantly, NS-398, a selective COX-2 inhibitor, effectively prevents cognitive deficits in mice and reduction in cell viability of human neurons associated with these chemotherapies, without promoting tumor growth or interfering with cisplatin’s anti-tumor activity. Taken together, our findings strongly suggest that COX-2 induction is a main cause of CICI, making COX-2 inhibition a therapeutic target for CICI. Given that COX-2 inhibitors are currently being tested in cancer prevention as well as age-related memory loss in clinical trials, inhibiting COX-2 may have far-reaching therapeutic effects on CICI and cancer treatment, which can be applied quickly, safely, and effectively to clinical trials, in the effort to improve cancer survivor quality of life. Citation Format: Mohammad Abdur Rashid, Jason J. Tang, Ki-Hyun Yoo, Ana Corujo-Ramirez, Sang Hoon Kim, Alfredo Oliveros, Peter Cole, John R. Hawse, Mi-Hyeon Jang. Blockade of the cyclooxygenase-2 prevents chemotherapy-induced cognitive impairments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2694.

Background and Aims: Biliary tract cancers are rare, heterogeneous cancers with poor prognoses. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β “trap”) fused to a human IgG1 monoclonal antibody blocking programmed death ligand 1, was evaluated in patients with locally advanced/metastatic chemorefractory biliary tract cancers. Approach and Results: This multicenter, single-arm, open-label, phase 2 study (NCT03833661) enrolled adults with locally advanced or metastatic biliary tract cancer that was intolerant to or had failed first-line systemic platinum-based chemotherapy. Patients received 1200 mg bintrafusp alfa intravenously Q2W. The primary endpoint was confirmed objective response according to Response Evaluation Criteria in Solid Tumors 1.1 assessed by IRC. Secondary endpoints included duration of response, durable response rate, safety, progression-free survival, and overall survival. Between March 2019 and January 2020, 159 patients were enrolled. Median follow-up was 16.1 (range, 0.0–19.3) months; 17 patients (10.7%; 95% CI: 6.4%–16.6%) achieved an objective response. Median duration of response was 10.0 (range, 1.9–15.7) months; 10 patients (6.3%; 95% CI: 3.1%–11.3%) had a durable response (≥6 mo). Median progression-free survival was 1.8 months (95% CI: 1.7–1.8 mo); median overall survival was 7.6 months (95% CI: 5.8–9.7 mo). Overall survival rates were 57.9% (6 mo) and 38.8% (12 mo). Grade ≥3 adverse events occurred in 26.4% of patients, including one treatment-related death (hepatic failure). Frequent grade ≥3 adverse events included anemia (3.8%), pruritus (1.9%), and increased alanine aminotransferase (1.9%). Conclusions: Although this study did not meet its prespecified primary endpoint, bintrafusp alfa demonstrated clinical activity as second-line treatment in this hard-to-treat cancer, with durable responses and a manageable safety profile.

Abstract Background: Oncogenic alterations (gene amplification, mutation, and fusion/rearrangements) of fibroblast growth factor receptor 2 (FGFR2) are rare and occur at varying frequencies across solid tumor types and have become critical therapeutic targets in drug development. First generation FGFR pan-kinase inhibitors non-selectively inhibit FGFR1-4 and are associated with dose limiting toxicities and narrow therapeutic windows. Off-isoform toxicity (FGFR1-hyperphosphatemia; FGFR4-diarrhea) and on-target acquired resistance have led to limited efficacy, which is primarily seen in FGFR2-fusion+ intrahepatic cholangiocarcinoma. Therapies that selectively target FGFR2 remain an unmet need in advanced breast cancer as well as other solid tumor types. RLY-4008 is a novel, oral FGFR2 inhibitor designed to overcome the limitations of pan-FGFR inhibitors (FGFRi) by potently and selectively targeting primary oncogenic FGFR2 alterations and acquired resistance mutations. RLY-4008 is &gt; 200-fold selective over FGFR1, &gt; 80- and &gt; 5000-fold selective over FGFR3 and FGFR4 respectively. Here we describe a phase 1/2 study to investigate the safety and antitumor activity in advanced FGFR2 altered cancers, including breast cancer. Methods: ReFocus is a phase 1/2 open label global study evaluating the safety and efficacy of RLY-4008 (NCT04526106) in adult patients with advanced unresectable and/or metastatic cancers harboring an FGFR2 alteration. Key eligibility criteria include: documented FGFR2 alteration in blood or tissue per local assessment, ECOG performance status of 0-1, disease that is refractory or not adequately responding to standard therapy, has no available standard therapy, or patient is intolerant of, or declined standard therapy (including pan-FGFRi), and measurable or evaluable disease per RECIST 1.1. FGFR2 alteration will be confirmed retrospectively by central laboratory assessment. Part 1 dose escalation employed the Bayesian Optimal Interval (BOIN) design to determine the MTD/RP2D of RLY-4008. Part 2 dose expansion is presently enrolling patients at the RP2D of RLY-4008 and includes 5 cohorts comprised of patients with: 1. FGFR2 fusion+ cholangiocarcinoma previously treated with an FGFRi; 2. FGFR2 fusion+ cholangiocarcinoma not previously treated with an FGFRi; 3. FGFR2 fusion+ solid tumors; 4. FGFR2 mutation+ solid tumors and 5. FGFR2 amplified solid tumors. Solid tumors in cohorts 3, 4 and 5 will have a focus in breast cancer. The primary endpoint is objective response rate (ORR); key secondary endpoints include: duration of response, safety and tolerability, correlation of FGFR2 genotype by central tissue assessment with antitumor response, characterization of PK profile, and quality of life. US enrollment began September 2020 and has expanded into Europe and Asia. Clinical trial information: NCT04526106. Citation Format: Suneel Kamath, David Tai, Irene Moreno, Hani Babiker, Zhaohui Jin, Changhoon Yoo, Fabien Ricard, Kai Yu Jen, Jim Coward, Jia Liu, Frans Opdam, Michael Millward, Mariano Ponz-Sarvise, Jeffrey Yachnin, Richard Kim, Joon Oh Park, Vivek Subbiah, Alison M. Schram. ReFocus: A Phase 1/2 Study of the Highly Selective FGFR2 Inhibitor, RLY-4008, in Patients with Advanced Solid Tumors Including Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-24-01.

Despite the proven benefit of stent retrievers, challenges to rapid revascularization of large vessel occlusions (LVO) persist. Current stent retrievers have limited effectiveness for removing organized thrombi. The NeVa device is a novel stent retriever designed with openings in the basket cell structure (“drop zones”) intended to capture organized thrombi within the central scaffold during retrieval. Prospective, multicenter, open label, single arm, FDA-regulated IDE study to evaluate the performance of the NeVa device for recanalizing occluded intracranial vessels including ICA, M1/M2 MCA, and vertebrobasilar arteries, within 8 hours of onset. Primary endpoint was rate of eTICI 2b-3 within 3 NeVa passes, tested for non-inferiority against a performance goal of 72% with a margin of -10%. Additional efficacy endpoints included first pass effect to eTICI 2b-3 (FPE) and 90-day mRS 0-2. Primary safety endpoint was 90-day mortality. (ClinicalTrials.gov NCT04514562) (Site-adjudicated revascularization results are reported here. Final core lab results will be presented at the conference.) From April 1, 2021 to April 28, 2022, 139 subjects were enrolled at 25 centers in the US and Europe. Mean age was 67 ± 13 years; 47% were female. Median NIHSS score was 16 (IQR: 12-20). Occlusions were 14 (10%) ICA, 85 (61%) M1, 38 (27%) M2, 1 (1%) Basilar and 1 (1%) PCA. Mean time to first pass was 19 ± 12 minutes. eTICI 2b-3 within 3 NeVa passes occurred in 87.8% (122/139; CI 81.1%,92.7%; non-inferiority p<0.0001; post hoc superiority p=0.002, tested against performance goal of 72%). FPE (to eTICI 2b-3) was observed in 67.6% (94/139), with first pass to eTICI 2b67-3 in 61.2% (85/139) and to eTICI 2c-3 in 43.9% (61/139). Median number of passes was 1 (IQR 1-2). Final eTICI 2b-3 rate was 94.2% (131/139); final eTICI 2c-3 rate was 65.5% (91/139). Good outcome (90-day mRS 0-2) was seen in 62.6% (87/139) and was 74.4% in patients with FPE (70/94 vs. 17/45 (37.8%) without FPE; p<0.0001). Mortality was 9.4% (13/139) with sICH in 8 (5.8%) subjects. The NeVa device is effective and safe for revascularization of LVO strokes and demonstrates high first pass success in this international multicenter study. First pass reperfusion (eTICI 2b-3) was strongly associated with functional independence.