bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B036: Micromechanical regulation of tumor immune microenvironment
Authors: Peura Aino , Turpin Rita , Salmela Maria , Liu Ruixian , Mikkonen Piia , Klefström Juha , Munne Pauliina M
Published: February 2024

Although the prognosis of primary breast cancer (BC) is considerably good, the prognosis of therapy-resistant, metastatic BC remains rather poor, thus being the major cause of BC-related deaths. Due to the undifferentiated and heterogenous nature of this disease, immunotherapies have been among the most promising therapeutic strategies for metastatic BC. However, in recent clinical trials, immunotherapies have had a poor success rate for breast cancer. Therefore, new therapeutic strategies and more profound knowledge of BC-specific immune-evasion mechanisms are urgently needed. We have developed a patient-derived explant model (PDEC), that allows us to cultivate patient-derived primary tumor samples. Moreover, the model also maintains alive the tumor resident immune cells, hence providing us with a unique platform for researching immunological drugs in vivo. In our model, tumor cells and tumor-derived immune cells are embedded in a 3D scaffold matrix with altering biological and physical properties. By altering the material in which the tumor cells are embedded we can also research the effect of microenvironmental factors such as stiffness and growth factors on the tumor cells. Microenvironmental stiffness is a well-known regulator of BC identity; in stiff 3D microenvironment breast cancer cells maintain their original identity, while in a softer microenvironment, they dedifferentiate towards more undifferentiated, therapy-resistant, and metastasis-mimicking subtype (Munne et al, 2021). In this study, we observed for the first time how the alterations in breast tumor microenvironmental stiffness also alter the phenotype in the breast tumor immune microenvironment concomitantly. In the soft microenvironment, the cytokine profile is polarized towards more tumor suppressing via upregulation of TGFB and downregulation of IL1B. Moreover, immune response and antigen presentation are heavily downregulated. Lastly, macrophages are depolarized from M1-like toward more tumor-promoting. This effect is induced and mediated by tumor cells and fresh immune cells embedded in similar 3D conditions that fail to secrete tumor suppressive cytokines or silence antitumor immunity. Manipulation of the tumor cell identity and tumor immune microenvironment via alteration of 3D matrices provides us a unique perspective for observing new methods of how metastatic breast cancer creates immune evasion. Moreover, the model allows us to develop novel treatments against metastatic, theraphy resistant breast cancer and test them easily in ex vivo conditions.

Citation Format: Aino Peura, Rita Turpin, Maria Salmela, Ruixian Liu, Piia Mikkonen, Juha Klefström, Pauliina M Munne. Micromechanical regulation of tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B036.
Abstract B051: Breast cancer stem cells tolerate chromosomal instability during tumor progression via c-Jun/AXL stress signaling
Authors: Baba Shahnawaz A , Sun Qi , Mugisha Samson , Labhsetwar Shreyas , Klemke Richard , Desgrosellier Jay S
Published: February 2024

Chromosomal instability (CIN) is an important driver of tumor evolution and metastasis, yet its role in stemness remains unclear. Here, we describe CIN tolerance as a key attribute of stem-like cancer cells. We identified CIN as a critical stress induced during early tumor initiation that may pose a significant barrier limiting the growth of new tumors. While basal CIN levels were not sufficient to distinguish stem from non-stem cell types, CIN was upregulated in early-stage tumors from breast cancer stem cells in an activated signaling state, suggesting these cells could better tolerate this stress. Indeed, stem-like cell lines were more resistant to increased CIN compared to basal-like cells, despite similar baseline levels. Further, the CIN induced during early tumor initiation appears to be transient, as levels diminish in more established disease. Mechanistically, CIN resistance in stem-like cells is mediated by expression of the receptor tyrosine kinase AXL downstream of activated c-Jun stress signaling. Thus, CIN tolerance due to activation of c-Jun/AXL may be a defining feature of stemness, contributing to breast cancer progression.

Citation Format: Shahnawaz A Baba, Qi Sun, Samson Mugisha, Shreyas Labhsetwar, Richard Klemke, Jay S Desgrosellier. Breast cancer stem cells tolerate chromosomal instability during tumor progression via c-Jun/AXL stress signaling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B051.
Abstract IA11: Using the Cancer Dependency Map
Authors: Hahn William C
Published: February 2024

Although molecular profiling of human tumors is now routine, the use of this data to guide therapy remains limited to a subset of patients. To complement genome characterization studies, we have used genome scale gain and loss of function approaches to identify genes required for cell survival and transformation. Specifically, we have performed both genome scale RNAi and CRISRP-Cas9 screens in hundreds of cancer cell lines to identify differentially essential genes and the context that specifies gene dependency. These studies now allow us to define a Cancer Dependency Map. Using these datasets and approaches, we have defined new categories of potential cancer targets in breast and other cancers. In particular, we have interrogated genes required for MYC-driven breast cancers and identified metabolic dependencies in breast cancers and identified a novel mechanism of estrogen receptor expression. These approaches promise to further operationalize precision cancer medicine.

Citation Format: William C Hahn. Using the Cancer Dependency Map [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA11.
Abstract IA26: Exploring breast cancer vulnerabilities through apoptotic pathways
Authors: Whittle James R , Vaillant François , Surgenor Elliot , Heitink Luuk , Muttiah Christine , Visvader Jane E , Lindeman Geoffrey J
Published: February 2024

Combined CDK4/6 inhibitor and endocrine therapy has rapidly become standard therapy for patients with early line relapsed estrogen receptor (ER)-positive, HER2-negative breast cancer. Although this combination has been shown to significantly improve progression free and overall survival, relapse is virtually inevitable. This may in part be due to the profound cytostatic effect of CDK4/6 inhibitors on tumors, which is associated with reduced apoptotic cell death. It seems likely that growth arrested and/or senescent tumor cells acquire resistance to therapy, leading to relapse. BH3 mimetics are an emerging class of drug that target pro-survival proteins such as BCL2, BCL-xL and MCL1. Venetoclax, a BH3 mimetic that has potent and specific activity against BCL2, has shown considerable promise in hematopoietic tumors such as CLL, but has yet to be fully explored in solid tumors. We have previously demonstrated safety and efficacy of combining tamoxifen with venetoclax for patients with metastatic ER-positive BCL2-positive disease using pre-clinical PDX models and a dose-finding phase 1 study [mBEP study, ISRCTN98335443], where most patients were CDK4/6 inhibitor therapy-naïve. In the post-CDK4/6 inhibitor setting, however, venetoclax did not improve clinical benefit rate or progression free survival when added to fulvestrant in the phase 2 study VERONICA [NCT03584009]. In that study a minority of tumours exhibited strong BCL2 expression and exploratory biomarker analysis revealed a trend towards improved progression free survival for patients with tumors exhibiting high BCL2 expression (IHC 3+), a BCL2:BCL-xL Histoscore ratio ≥1, or with PIK3CA wild-type status. Using pre-clinical models including patient derived xenografts of ER-positive breast cancer, we have shown that the addition of venetoclax to dual therapy comprising fulvestrant and the CDK4/6 inhibitor palbociclib elicits a superior and more durable tumor response, accompanied by increased apoptosis. These findings have formed the basis of a phase 1 clinical trial of palbociclib, letrozole and venetoclax [PALVEN, NCT03900884] in patients with early line relapsed ER and BCL2-positive metastatic breast cancer. In parallel, pre-clinical studies are underway to determine the effect of dual targeting BCL-xL and MCL1, as well as dual targeting of AKT and with a BH3 mimetic in CDK4/6 inhibitor refractory breast cancer cells.

Citation Format: James R Whittle, François Vaillant, Elliot Surgenor, Luuk Heitink, Christine Muttiah, Jane E Visvader, Geoffrey J Lindeman. Exploring breast cancer vulnerabilities through apoptotic pathways [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA26.
Abstract PR10: Mammary epithelial architecture modulates field cancerization
Authors: Messal Hendrik A , Cleyp0ol Cindy , Lutz Catrin , Hutten Stefan , Lips Esther , Jonkers Jos , Wesseling Jelle , Bleys Ronald , Simons Ben , Scheele Colinda , van Rheenen Jacco
Published: February 2024

The architecture of the human breast undergoes extensive remodelling throughout puberty, the menstrual cycle, pregnancy, and involution with a risk of accumulating genetic alterations and tissue changes. Cells with mutations in cancer driver genes are abundant in tissues of healthy individuals, but rarely develop into tumors. However, the underlying mechanisms that prevent tumor formation are largely unknown. We utilized tissue clearing and imaged 15 disease-free human breasts and cancer resections with subcellular resolution to unravel the 3D architecture of thousands of mammary ducts per individual. Surprisingly, our analysis revealed that disease-free breasts carry a high burden of microscopic tissue lesions indicating widespread abnormal cell behaviour. Distinct mammary trees from the same breast differed in the kind and frequency of lesions, which coevolved scattered along the ductal routes. Combining 3D imaging of FFPE archived breast cancer resections with spatial CNV-seq revealed that, in half the cases, disease-free ductal segments neighbouring early cancer lesions contain molecular alterations. To resolve the mechanisms that regulate mutation spread, we compared the clonal behavior of cells with oncogenic mutations and neutral mutations in the mouse mammary gland epithelium. From the analysis of the clonal dynamics, we find that local tissue remodeling during the estrous cycle leads to the elimination of the majority of mutant clones, while accelerating the expansion of surviving clones. Thus, oncogenic mutations can spread along entire ducts before signs of transformation become apparent. Our data provides understanding of the earliest stages of epithelial evolution preceding disease.

Citation Format: Hendrik A Messal, Cindy Cleyp0ol, Catrin Lutz, Stefan Hutten, Esther Lips, Jos Jonkers, Jelle Wesseling, Ronald Bleys, Ben Simons, Colinda Scheele, Jacco van Rheenen. Mammary epithelial architecture modulates field cancerization [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr PR10.
Abstract A011: Modeling the coevolution of native and CAR T-cells in large B cell lymphoma reveals a potential biomarker for response to therapy
Authors: Gatenbee Chandler D. , Robertson-Tessi Mark , Strobl Maximilian , Schenck Ryan O. , Ziccheddu Bachisio , Maura Francesco , Locke Frederick , Anderson Alexander R.A.
Published: February 2024

Application of CD19 targeted Chimeric Antigen Receptor (CAR) T-cell therapy to large B cell lymphoma (LBCL) has yielded unprecedented clinical outcomes in a cancer largely resistant to conventional chemotherapy. This is highlighted in the recent ZUMA-7 trial, where axicabtagene ciloleucel (axi-cel), a CAR T-cell therapy, yielded a complete response (CR) rate in 65% of patients, an improvement over the 32% CR rate when using standard chemotherapy. The ZUMA-7 trial highlights the potential of CAR T-cell therapy to treat traditionally resistant cancers, but work remains to be done to identify biomarkers predictive of response. Operating under the assumption that CAR T not only directly targets CD19+ tumor cells, but also enhances tumor kill by amplifying the native T-cell populations, we hypothesized that neoantigen burden (NAB) may serve as a useful biomarker to make predictions of response to CAR T. We explore this hypothesis by building upon traditional predator-prey mathematical models to simulate the evolution of LBCL under immune predation and treatment with CAR T-cell therapy. More specifically, in our model native T-cells prey upon tumor cells that carry their cognate neoantigen, and each T-cell has variable search rate proportional to the cognate neoantigen’s recognition potential, modeled using a type III functional response. Tumor cells may mutate during division, always gaining a neoantigen, but possibly also losing HLA function, paving the way for immune escape. In addition to modeling the direct killing of tumor by CAR T, we also explore the synergistic effect of CAR T on native T-cells by modeling increased amplification of, and killing by, native T-cells based on interactions with the CAR T-cell population. Preliminary simulations suggest a high NAB can indeed be predictive of CAR T response, although only if the tumor has not evolved an escape mechanism. Indeed, simulations suggest that high NAB can also be a signature of an immune escaped tumor, as neoantigens become neutral traits once the immune system is removed as a selective force. These results suggest that knowledge of a patients’ NAB and immune competency can be used to guide CAR T treatment decisions.

Citation Format: Chandler D. Gatenbee, Mark Robertson-Tessi, Maximilian Strobl, Ryan O. Schenck, Bachisio Ziccheddu, Francesco Maura, Frederick Locke, Alexander R.A. Anderson. Modeling the coevolution of native and CAR T-cells in large B cell lymphoma reveals a potential biomarker for response to therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A011.
Supplementary Figure S4 from Genome-wide p63-Target Gene Analyses Reveal TAp63/NRF2-Dependent Oxidative Stress Responses
Authors: Napoli Marco , Deshpande Avani A. , Chakravarti Deepavali , Rajapakshe Kimal , Gunaratne Preethi H. , Coarfa Cristian , Flores Elsa R.
Published: February 2024

∆Np63 and TAp63 control the expression of their common target genes together with Stat proteins
Prognostic Value of Left Ventricular Global Longitudinal Strain for Major Adverse Cardiovascular Events in Patients with Aortic Valve Disease: A Meta-Analysis
Authors: Liao Hongsheng , Yang Siyuan , Yu Shaomei , Hu Xuanyi , Meng XiongWei , Wu Kui
Published: February 2024

Introduction: Valvular heart disease is one of the most common heart diseases. It is characterized by abnormal function or structure of the heart valves. There may be no clinical symptoms in the early stages. Clinical symptoms of arrhythmia, heart failure, or thromboembolic events may occur in the late stages of the disease, such as palpitation after activities, breathing difficulties, fatigue, and so on. Aortic valve disease is a major part of valvular heart disease. The main treatment for aortic valve disease is valve replacement or repair surgery, but it is extremely risky. Therefore, a rigorous prognostic assessment is extremely important for patients with aortic valve disease. The global longitudinal strain is an index that describes the deformation capacity of myocardium. There is evidence that it provides a test for systolic dysfunction other than LVEF (left ventricular ejection fraction) and provides additional prognostic information. Method: Search literature published between 2010 and 2023 on relevant platforms and contain the following keywords: “Aortic valve disease,” “Aortic stenosis,” “Aortic regurgitation,” and “longitudinal strain” or “strain.” The data is then extracted and collated for analysis. Results: A total of 15 articles were included. The total population involved in this study was 3,678 individuals. The absolute value of LVGLS was higher in the no-MACE group than in the MACE group in patients with aortic stenosis (Z = 8.10, p < 0.00001), and impaired LVGLS was a risk factor for MACE in patients with aortic stenosis (HR = 1.14, p < 0.00001, 95% CI: 1.08–1.20). There was also a correlation between impaired LVGLS and aortic valve surgery in patients with aortic valve disease (HR = 1.16, p < 0.0001, 95% CI: 1.08–1.25) or patients with aortic valve regurgitation (HR = 1.21, p = 0.0004, 95% CI: 1.09–1.34). We also found that impaired LVGLS had no significant association between LVGLS and mortality during the period of follow-up in patients with aortic valve stenosis (HR = 1.08, 95% CI: 0.94–1.25, p = 0.28), but it was associated with mortality in studies of prospective analyses (HR = 1.34, 95% CI: 1.02–1.75, p = 0.04). Conclusions: Impaired LVGLS correlates with major adverse cardiovascular events in patients with aortic valve disease, and it has predictive value for the prognosis of patients with aortic valve disease.
Waitlist Outcomes in Candidates With Rare Causes of Heart Failure After Implementation of the 2018 French Heart Allocation Scheme
Authors: Legeai Camille , Coutance Guillaume , Cantrelle Christelle , Jasseron Carine , Para Marylou , Sebbag Laurent , Battistella Pascal , Kerbaul François , Dorent Richard
Published: February 2024

BACKGROUND:

In 2018, an algorithm-based allocation system for heart transplantation (HT) was implemented in France. Its effect on access to HT of patients with rare causes of heart failure (HF) has not been assessed.

METHODS:

In this national study, including adults listed for HT between 2018 and 2020, we analyzed waitlist and posttransplant outcomes of candidates with rare causes of HF (restrictive cardiomyopathy [RCM], hypertrophic cardiomyopathy, and congenital heart disease). The primary end point was death on the waitlist or delisting for clinical deterioration. Secondary end points included access to HT and posttransplant mortality. The cumulative incidence of waitlist mortality estimated with competing risk analysis and incidence of transplantation were compared between diagnosis groups. The association of HF cause with outcomes was determined by Fine-Gray or Cox models.

RESULTS:

Overall, 1604 candidates were listed for HT. At 1 year postlisting, 175 patients met the primary end point and 1040 underwent HT. Candidates listed for rare causes of HF significantly differed in baseline characteristics and had more frequent score exceptions compared with other cardiomyopathies (31.3%, 32.0%, 36.4%, and 16.7% for patients with hypertrophic cardiomyopathy, RCM, congenital heart disease, and other cardiomyopathies). The cumulative incidence of death on the waitlist and probability of HT were similar between diagnosis groups (
P
=0.17 and 0.40, respectively). The adjusted risk of death or delisting for clinical deterioration did not significantly differ between candidates with rare and common causes of HF (subdistribution hazard ratio (HR): hypertrophic cardiomyopathy, 0.51 [95% CI, 0.19–1.38];
P
=0.18; RCM, 1.04 [95% CI, 0.42–2.58];
P
=0.94; congenital heart disease, 1.82 [95% CI, 0.78–4.26];
P
=0.17). Similarly, the access to HT did not significantly differ between causes of HF (hypertrophic cardiomyopathy: HR, 1.18 [95% CI, 0.92–1.51];
P
=0.19; RCM: HR, 1.19 [95% CI, 0.90–1.58];
P
=0.23; congenital heart disease: HR, 0.76 [95% CI, 0.53–1.09];
P
=0.14). RCM was an independent risk factor for 1-year posttransplant mortality (HR, 2.12 [95% CI, 1.06–4.24];
P
=0.03).

CONCLUSIONS:

Our study shows equitable waitlist outcomes among HT candidates whatever the indication for transplantation with the new French allocation scheme.
LncRNA CHKB-DT Downregulation Enhances Dilated Cardiomyopathy Through ALDH2
Authors: Nie Xiang , Fan Jiahui , Dai Beibei , Wen Zheng , Li Huaping , Chen Chen , Wang Dao Wen
Published: February 2024

BACKGROUND:

Human cardiac long noncoding RNA (lncRNA) profiles in patients with dilated cardiomyopathy (DCM) were previously analyzed, and the long noncoding RNA CHKB (choline kinase beta) divergent transcript (CHKB-DT) levels were found to be mostly downregulated in the heart. In this study, the function of CHKB-DT in DCM was determined.

METHODS:

Long noncoding RNA expression levels in the human heart tissues were measured via quantitative reverse transcription–polymerase chain reaction and in situ hybridization assays. A CHKB-DT heterozygous or homozygous knockout mouse model was generated using the clustered regularly interspaced palindromic repeat (CRISPR)/CRISPR-associated protein 9 system, and the adeno-associated virus with a cardiac-specific promoter was used to deliver the RNA in vivo. Sarcomere shortening was performed to assess the primary cardiomyocyte contractility. The Seahorse XF cell mitochondrial stress test was performed to determine the energy metabolism and ATP production. Furthermore, the underlying mechanisms were explored using quantitative proteomics, ribosome profiling, RNA antisense purification assays, mass spectrometry, RNA pull-down, luciferase assay, RNA–fluorescence in situ hybridization, and Western blotting.

RESULTS:

CHKB-DT levels were remarkably decreased in patients with DCM and mice with transverse aortic constriction–induced heart failure. Heterozygous knockout of CHKB-DT in cardiomyocytes caused cardiac dilation and dysfunction and reduced the contractility of primary cardiomyocytes. Moreover, CHKB-DT heterozygous knockout impaired mitochondrial function and decreased ATP production as well as cardiac energy metabolism. Mechanistically, ALDH2 (aldehyde dehydrogenase 2) was a direct target of CHKB-DT. CHKB-DT physically interacted with the mRNA of ALDH2 and fused in sarcoma (FUS) through the GGUG motif. CHKB-DT knockdown aggravated ALDH2 mRNA degradation and 4-HNE (4-hydroxy-2-nonenal) production, whereas overexpression of CHKB-DT reversed these molecular changes. Furthermore, restoring ALDH2 expression in CHKB-DT
+/
−
mice alleviated cardiac dilation and dysfunction.

CONCLUSIONS:

CHKB-DT is significantly downregulated in DCM. CHKB-DT acts as an energy metabolism-associated long noncoding RNA and represents a promising therapeutic target against DCM.
Abstract 118: Vagus Nerve Stimulation Paired With Rehabilitation for Post-Stroke Arm Impairment: One Year Follow-Up of the VNS-REHAB Pivotal Trial
Authors: Kimberley Teresa J , Cramer Steven C , Wolf Steven L , Liu Charles , Dawson Jesse ,   VNS-REHAB Pivotal Trial Study Group
Published: February 2024

Background:
Persistent post-stroke impairment of the arm and hand is debilitating after stroke. Pairing vagus nerve stimulation (VNS) with upper extremity (UE) rehabilitation improves such deficits after 5 months and was approved by the FDA in 2021. Here, we present 1-year outcomes from the VNS-REHAB pivotal trial.

Methods:
Stroke participants with moderate-to-severe UE impairment were randomized to task-specific rehabilitation plus either active VNS (n=53, VNS) or sham VNS (n=55, Control). After baseline assessment (Pre-therapy), both groups did 6 wk. of in-clinic therapy followed by a 3-mo. home exercise program combined with active or sham VNS (post90). Controls then crossed over to receive 6 wk. of active VNS followed by a 3-mo. home exercise program (Cross-over post90). Both groups continued active VNS with a home exercise program through 1 year, after which change from Pre-therapy baseline in Fugl-Meyer Assessment-Upper Extremity (FMA-UE) and Wolf Motor Function Test (WMFT) scores were obtained. To determine whether participants made additional gains, 1 year outcome scores (n=70) were also compared to post90 (n=38, VNS) and Cross-over post90 (n=32, Control) scores. Data was available from 74 participants at one year, with others not available mainly due to COVID-19.

Results:
At 1-year, both FMA-UE and WMFT scores improved from Pre-therapy baseline by 5.3±6.9 (CI=3.7-6.9, p<0.001) and 0.51±0.52 (CI=0.39-0.63, p<0.001) points, respectively. FMA-UE change at 1-year was not significantly different from the post90 (VNS) and Cross-over post90 (control) timepoints (n=70, mean difference: -0.3±4.1, CI=-1.3-0.67, p=0.52), but WMFT was, by an additional 0.09 points (n=70, mean difference: 0.09±0.35, CI=0.01-0.18, p=0.03), indicating that participants either improved or maintained motor gains through 1 year.

Conclusion:
Improvements in arm and hand function with VNS were maintained at 1-year follow-up, supporting use of VNS paired with rehabilitation as a long-term treatment option for individuals with post-stroke UE impairment. Limitations include sample size and lack of details of therapeutic regimens over the long term. Future studies and an ongoing clinical registry will explore the long-term impact of active VNS in real-world settings.
Abstract 66: Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in Atrial Fibrillation: Primary Results of the START Trial
Authors: Warach Steven J , Davis Lisa A , Lawrence Patrick , Gajewski Byron , Wick Jo , Shi Fred , Fabian Roderic , Shang Ty T , Olson Daiwai M , Prasad Sidarrth , Birnbaum Lee , Richardson Jody M , Goldberg Mark P , Savitz Sean I , Cruz-Flores Salvador , Alba Israel , Anderson Jane , Kimmel Barbara , Venkatasubba Chethan P , King Ben , Dula Adrienne N , Milling Truman J ,   Lone Stroke Stroke Rsch Consortium
Published: February 2024

Introduction:
Clinical practice guidelines recommend initiation of anticoagulation within 2 weeks after stroke due to atrial fibrillation (AF). It is unknown whether there is an optimal day within that 14-day period that balances the risks of recurrent embolic vs serious hemorrhagic events.

Methodology:
The Lone Start Stroke START trial is a pragmatic, prospective, multi-center, response-adaptive randomized Phase 2 study of 200 patients prescribed a direct oral anticoagulant (DOAC) for secondary prevention of stroke due to AF. Patients were randomized into one of 4 Arms: Day 3-4 from stroke onset, Day 6, Day 10, or Day 14. The primary outcome was an ischemic (stroke or systemic embolus) or hemorrhagic (ICH or major systemic hemorrhage) event observed within 30 days from the index stroke time of onset. Posterior probabilities that each arm was the best were calculated at predefined intervals and randomization allocations were adjusted to favor the Arms with higher probabilities.

Results:
The median age was 75 (IQR 65-81), median NIHSS at presentation was 7 (IQR 4-14), median lesion diameter was 3.1 cm (IQR 2.0-4.4) at the time of randomization. The sample was 50% female, 17.5% non-white, and 16.5% Hispanic. Apixaban was the prescribed DOAC in 89% of the patients. No ischemic events were observed for Arm 1, and no hemorrhage events were observed for Arm 4. Arm 1 (3-4 days) had a posterior 41.1% probability of being the best among the four, with probabilities of 26.4%, 17.1%, and 15.4 % respectively, for the other arms. Response adapted randomization was feasible and favored the earlier two arms. Expected event rates for each arm are presented in the Table. The timing and severity of the outcome events will be presented at the conference.

Conclusion:
Although the START trial did not identify a clearly superior day to initiate DOAC for secondary stroke prevention in AF, the evidence suggests that initiating DOAC early is better than at later times within the first 2 weeks after stroke onset.
Abstract 82: The Association of Transfer Status and Time on Clinical and Imaging Outcomes in Large Core Strokes:
A SELECT2 Subanlaysis
Authors: Sarraj Amrou , Abraham Michael G , Chen Michael , Kasner Scott E , Ortega-Gutierrez Santiago , Hussain Muhammad S , Pujara Deep , Shaker Faris , Churilov Leonid , Sundararajan Sophia , Hu Yin , Al-Shaibi Faisal , Opaskar Amanda , Duncan Kelsey R , Moussa Rami , Johns Hannah , Abdulrazzak Mohammad A , Blackburn Spiros , DeGeorgia Michael , Bambakidis Nicholas C , Sila Cathy A , Mendes Pereira Vitor , Lansberg Maarten G , Albers Gregory W , Hill Michael , Grotta James C , Ribo Marc , Hassan Ameer E , Campbell Bruce ,   The SELECT2 Investigators
Published: February 2024

Background:
Patients with large core strokes have poor clinical outcomes and are frequently not transferred to endovascular thrombectomy (EVT)-capable centers for EVT. We analyzed the association of transfer status and time on neuroimaging changes, clinical outcomes and EVT treatment effect in SELECT2.

Methods:
Patients enrolled in the SELECT-2 trial were stratified based on transfer status. CT ASPECTS at outside hospital and EVT center were collected if available. Treatment effect was compared by transfer status as well as in transferred patients with outside ASPECTS ≤5. The association of ASPECTS loss during transfer was also quantified. The primary outcome was the distribution of modified Rankin Scale score at 90-day follow-up.

Results:
Of 352 enrolled patients, 211 (60%) were transferred to EVT capable center and 108(51%) received EVT. 141 presented directly and 72 (51%) received EVT. The median transfer time was 185 (140-234) minutes. Median ASPECTS decreased from outside hospital [5(4-7)] to EVT center [4 (3-5)] with ASPECTS decay rate at 0.31 (0-0.84) points/hour of transfer time, with 50/120 (42%) experienced ASPECTS loss ≥2. Thrombectomy treatment effect was preserved in both directly presenting patients [aGenOR: 2.01 (1.42-2.86)] as well as transferred patients [aGenOR: 1.50 (1.11-2.03)] without significant heterogeneity (P-int=0.14). EVT also demonstrated numerically better functional outcomes in transferred patients with outside ASPECTS of ≤5 (n=65, 35 EVT, aGenOR: 1.77 (0.97-3.23), p=0.068). ASPECTS loss was associated with worse clinical outcomes in EVT [aGenOR: 0.81 (0.71-0.83) per ASPECTS point loss] but not in MM: [aGenOR: 0.89 (0.73-1.08) per ASPECTS point loss].

Conclusion:
In large core patients, transfer time was associated with ASPECTS decay, resulting in worse outcomes with EVT. Transferred patients however still benefited from EVT, with a trend towards better outcomes in patients with low ASPECTS at outside hospitals. These findings may substantially impact stroke care infrastructure, emphasizing the need for rapid identification of patients suitable for transfer and expedited transport.

Clinicaltrials.gov registration:
NCT03876457
Abstract TMP54: Persistent Penumbral Profiles Indicate a Potentially Good Outcome in Acute Stroke Patients Without Major Reperfusion
Authors: Hong Lan , Lin Longting , Chen Chushuang , Bivard Andrew , Levi Christopher R , Su Ya , Ling Yifeng , Parsons Mark W , Cheng Xin , Dong qiang ,   INSPIRE Study Group
Published: February 2024

Background:
It is acknowledged that penumbra can exist beyond 24 hours after stroke onset. The aim of this study was to explore the association between penumbral persistence at 24-72 hours and clinical outcomes in patients who did not achieve major reperfusion.

Methods:
Eligible patients participating in the International Stroke Perfusion Imaging Registry with repeated 24-72 hours perfusion imaging were included in this study. Persistent penumbra was evaluated as the volume of hypoperfusion lesion on repeated perfusion imaging divided by infarct volume on the follow-up imaging at 24-72 hours post arrival. Short-term clinical outcomes were defined as neurological deterioration at 24-72 hours and modified Rankin Scale (mRS) 0-2 at discharge. Long-term outcome was defined as mRS 0-2 at 3 months. The association between persistent penumbra and clinical outcomes was explored using multivariable-adjusted logistic regression models.

Results:
A total number of 203 patients were included in this study. Persistent penumbra was associated with decreased odds of neurological deterioration at 24-72 hours (multivariable-adjusted OR=0.3, P=0.01) and increased odds of mRS 0-2 at 3 months (multivariable-adjusted OR=2.7, P=0.03). Persistent penumbra was not associated with mRS 0-2 at discharge (multivariable-adjusted OR=2.5, P=0.30).

Discussion:
Persistent penumbra in acute stroke patients without major reperfusion was generally associated with a better clinical outcome. This evidence suggested that there were patients with persistent hemodynamic support, for whom major reperfusion might not be pivotal to achieve a good clinical outcome. How to identify these patients and what treatment strategy can be made to stabilize the hemodynamics need future investigation.
Abstract TMP60: Contralesional Brain Regions Mirror the Volume Changes of Their Homologous Counterparts in the Ipsilesional Hemisphere in Children During the First Year After Unilateral Intracerebral Hemorrhage
Authors: Choi Hannah L , Mahuvakar Shivani , Cai Lanya T , Kim Helen , Saloner David A , Fox Christine K , Roland Jarod , Fullerton Heather J , Mukherjee Pratik ,   UCSF AHA Bugher Hemorrhagic Stroke Rsch Group
Published: February 2024

Introduction:
Structural changes following intracerebral hemorrhage (ICH) caused by ruptured brain vascular malformations (VMs) remain poorly understood. We conducted a longitudinal study to examine changes across ipsilesional and contralesional hemispheres after unilateral ICH, mainly in the temporoparietal area.

Methods:
Brain MRI was acquired in 8 patients aged 8-18 years (
Mean
=15.13,
SD
=3.18) at presentation of ICH prior to treatment (baseline/Session 1) and repeated at 6 months (Session 2) and 12 months (Session 3) post-treatment. Using FreeSurfer 7.4.0, T1 and T2 FLAIR MR images were segmented into cortical and subcortical regions, with gray matter (GM) parcellated based on the DKT atlas. SynthSeg refined lesion extraction for more precise measurements of brain volume. Volume changes were quantified as percent change from baseline with signed values denoting increase or decrease. Pearson correlation and permutation testing (
n
=5000) evaluated associations of homologous versus non-homologous regions.

Results:
There were significant correlations between the volume changes of homologous GM regions, for both Session 2 (
R
=0.57,
p
<0.001) and Session 3 (
R
=0.50,
p
<0.001), and of homologous GM in hemispheric lobes (Session 2:
R
=0.69,
p
<0.001; Session 3:
R
=0.67,
p
<0.001). Permutation tests confirmed that correlations of volume changes were greater for homologous than non-homologous regions and lobes for Sessions 2 and 3 (
p
<0.001 except Session 3 lobes:
p
=0.016).

Conclusions:
We observed structural covariance of volume changes between homologous regions, most pronounced in the first 6 months after unilateral ICH. This indicates network-mediated distant effects of ICH, with atrophy reflected by diaschisis and volume recovery mirrored by positive neuroplasticity of contralateral homologs. Lesion-network mapping with correlation to long-term outcome would elucidate the effects of this long-range neuroplasticity following pediatric ICH.
Abstract TMP77: Oral Health as a Risk Factor for Spontaneous Intracerebral Hemorrhage: A Mendelian Randomization Analysis
Authors: Rivier Cyprien , Clocchiatti-Tuozzo Santiago , Huo Shufan , Renedo Daniela , Sunmonu N. Abimbola , Hawkes Maximiliano , Sheth Kevin N , Falcone Guido J
Published: February 2024

Background:
Poor oral health is a highly prevalent and modifiable risk factor that is associated with higher risk of cardiovascular disease, including ischemic stroke. However, the relationship between oral health and spontaneous intracerebral hemorrhage (ICH) has not been studied. We tested the hypothesis that genetically-determined poor oral health increases the risk of ICH.

Methods:
We conducted a two-sample Mendelian Randomization (MR) study using summary statistics from the largest genome-wide associations studies of oral health and ICH conducted to date. As genetic instruments (e.g., genetic risk variants for oral health), we identified 105 independent single nucleotide polymorphisms known to be associated with higher risk of caries, dentures and missing teeth at genome wide levels (p<5x10
-8
). The primary analysis employed summary statistics-based MR to assess the relationship between poor oral health and risk of ICH in any brain location. Secondary analyses evaluated deep and lobar ICH separately.

Results:
The primary analysis using the inverse variance-weighted MR method showed that genetically-increased risk of poor oral health was associated with a higher risk of ICH (OR 2.34, [1.08-5.06], p=0.029). Secondary analyses indicated a more potent association with deep ICH (OR 3.20 [1.34-7.6], p=0.008), whereas the link with lobar ICH was not statistically significant (OR 1.32 [0.53-3.27], p=0.543). Sensitivity analyses detected no horizontal pleiotropy in our findings (MR-PRESSO global test p-values >0.05).

Conclusion:
Genetically-determined poor oral health is associated with an increased risk of ICH, particularly in the case of deep ICH. Because gene-disease associations are less prone to confounding, our results suggest that this association is causal. However, further analyses are needed to validate these results and identify the mediating mechanisms. Because oral health is an easily modifiable process, it may be a promising target for very early interventions focused on mitigating the risk of hemorrhagic stroke.
Abstract TMP93: Severe Non-Contrast CT Hypodensity Modifies EVT Treatment Effect and is Associated With Worse Outcomes Independent of Ischemic Core Volume:
A Secondary Analysis of the SELECT2 Trial
Authors: Yogendrakumar Vignan , Johns Hannah Tabitha , Churilov Leonid , Ng Felix , Hassan Ameer E , Abraham Michael G , Ortega-Gutierrez Santiago , Hussain M. Shazam , Chen Michael , Sitton Clark , Kasner Scott , Guha Prodipta , Sharma Gagan J , Pujara Deep K , Mendes Pereira Vitor , Lansberg Maarten G , Wechsler Lawrence , Nguyen Thanh , Hill Michael D , Ribo Marc , Parsons Mark W , Davis Stephen M , Grotta James C , Albers Gregory W , Campbell Bruce , Sarraj Amrou ,   SELECT2 Investigators
Published: February 2024

Introduction:
Endovascular thrombectomy (EVT) reduces disability in patients with large ischemic core stroke. Increasing core volume is prognostic but does not modify treatment effect. CT hypodensity can vary within an area of core. We assessed the relationship between the severity of CT core hypodensity and clinical outcome in the SELECT2 trial.

Methods:
Non-contrast CT ischemic core was drawn manually by two blinded investigators with consensus review by a third investigator. An absolute Hounsfield unit (HU) threshold for severe hypodensity was set at the lower 99% confidence interval [CI] for normal contralateral thalamic grey matter. Outcomes assessed included ordinal mRS, functional independence (mRS 0-2), independent ambulation (mRS 0-3), and mortality at 90 days. The association between the volume of severe hypodensity and outcome was adjusted for age, baseline NIHSS, and total baseline core volume, via logistic and proportional odds models with treatment*hypodensity interaction.

Results:
Of 317 assessable patients, the median hypodensity of ischemic core was 31HU (IQR 28-33). Median density of normal thalamus was 38HU. The severe hypodensity threshold (lower 99% CI) was 26HU with median volume affected 14mL (IQR 5.6-29.2) or median 19% (IQR 9-35%) of the total hypodensity volume. The volume of core ≤26HU (per 1 mL increase) was associated with a 90-day mRS shift towards worse outcomes in EVT patients (n=161, adjusted common odds ratio, acOR 1.03, 95%CI 1.01-1.05) but not medical management ([MM], n=156, acOR 1.00, 95%CI 0.98-1.02, p-interaction 0.005); lower functional independence in EVT (aOR 0.96 95%CI 0.93-0.99) but not MM (aOR 1.02, 95%CI 0.99-1.06, p-interaction 0.004); lower independent ambulation in EVT (aOR 0.97, 95%CI 0.94-0.99) but not MM (aOR 1.01, 95%CI 0.98-1.04, p-interaction 0.002) and higher mortality in EVT (aOR 1.03, 95%CI 1.01-1.05) but not MM (aOR 1.00, 95%CI 0.98-1.02, p-interaction 0.02).

Conclusion:
In patients with large ischemic core, areas of significant CT hypodensity are associated with worse clinical outcomes after EVT but not MM. This is independent of total core volume and modifies the treatment effect of EVT. This may improve prognostic decision-making and drive developments in automated image processing.
Abstract TP8: Gender Differences in Intracranial Aneurysms
Authors: Uchida Kazutaka , Matsukawa Hidetoshi , Sowlat Mohammad-Mahdi , Elawady Sameh S , Alawieh Ali , Jabbour Pascal M , Mascitelli Justin , Levitt Michael , Cuellar Hugo , Samaniego Edgar A , Kan Peter , Moss Mark , Spiotta Alejandro M , Yoshimura Shinichi
Published: February 2024

Background:
Some studies have shown that females had a poorer prognosis after endovascular treatment for ruptured intracranial aneurysm than males. However, data has been sparse regarding differences in the periprocedural and perioperative complication rates with ruptured and unruptured intracranial aneurysms.

Methods:
This retrospective cohort study used data from the Stroke Thrombectomy and Aneurysm Registry, a database of 9 institutions in the United States, Europe, and Asia. The study presented intracranial aneurysms after microsurgical and/or endovascular treatment from January 1, 2013 to December 31, 2022. The primary outcome was the incidence of periprocedural cerebral infarction. Secondary outcomes were periprocedural intracranial hemorrhage, periprocedural mortality, perioperative vasospasm, and functional outcome at 90 days after the procedure.

Results:
Among 3342 aneurysm patients, 2447 were female and 857 were male, mean age in females and male were 59.6 and 57.1. Current smoker, family history of aneurysm, and ruptured aneurysm were observed in 23.5% vs 35.7 %, 10.8 % vs 5.7%, and 28.2% vs 40.5% of female and male patients, respectively. In female patients, internal carotid artery aneurysms were more commonly observed (31.1% vs 17.3%), however, anterior cerebral artery aneurysm were less commonly observed (18.5% vs 33.8%) compared to male patients. Periprocedural cerebral infarction rate was lower in females than males (2.4% vs. 4.4%;
P
=
0.002). The adjusted odds ratio of primary outcome of female to male was 0.72 (95% CI, 0.46 - 1.12). Incidence of periprocedural Intracranial hemorrhage and periprocedural mortality, perioperative symptomatic vasospasm, and functional outcome were similar in both groups. In this analysis, periprocedural cerebral infarction due to microsurgical treatment occurred frequently in the male patients, while incidence in endovascular treatment was similar in both groups (interaction
P
= 0.005).

Conclusions:
This large multicenter registry of patients undergoing intracranial aneurysm treatment found that female patients were not at increased risk of perioperative complications.
Abstract WP119: Magnetic Resonance Imaging versus Computed Tomography Before Mechanical Thrombectomy for Acute Ischemic Stroke
Authors: Ohtsubo Haruki , Ueda Toshihiro , Hasegawa Yasuhiro , TAKEUCHI MASATAKA , MORIMOTO MASAFUMI , Tsuboi Yoshifumi , Yamamoto Ryoo , Shogo Kaku , Ayabe Junichi , Akiyama Takekazu , Ishima Daisuke ,   K-NET Registry Investigators
Published: February 2024

Introduction:
Magnetic resonance imaging (MRI) and computed tomography (CT) is useful for the evaluation of the ischemic core and penumbra. The indication for mechanical thrombectomy (MT) for acute ischemic stroke is determined by either or both imaging modalities. The selection of initial imaging modality is differed by the institute, and it is uncertain which imaging modality is superior before MT. In this study, we compared the clinical outcomes after MT by imaging modality in the K-NET registry (Kanagawa intravenous and endovascular treatment of acute ischemic stroke registry).

Methods:
The K-NET registry is a Japanese multicenter prospective registry study of patients treated with Intravenous thrombolysis with recombinant tissue plasminogen activator, endovascular treatment, or both for acute ischemic stroke. The present study is based on patients' data in the K-NET registry between January 2018 and June 2021. The inclusion criteria for the current analysis were as follows: (1) pre-modified Rankin score (mRS) 0-2; (2) patients transferred directly to primary stroke centers; (3) treated with MT; and (4) performed only CT or MRI for diagnosis of acute ischemic stroke before MT. The patients who performed both CT and MRI at admission were excluded. Unbalanced cohorts with a nonrandom distribution of patients were accounted for by using propensity score matching.

Results:
2348 patients were enrolled in the registry during the period, and 753 patients were eligible for inclusion criteria. 498 (249 matched pairs) were included after propensity score-matched analysis. The baseline characteristics were well-balanced between the two groups. There was no difference in the final mTICI grade between the two groups. The time from image to puncture in the MRI group was significantly shorter than the CT group (52min versus 38min), and the time from image to recanalization was also significantly shorter in the MRI group (108min versus 88.5min). The rate of functional independence (90 days mRS 0-2) was higher in the MRI group versus the CT group (54.4% versus 43.8%, p=0.017).

Conclusions:
The selection of MRI before MT was associated with a shorter time from image to puncture and recanalization and a favorable outcome compared with CT.
Diversity, Equity, and Inclusion Lessons From Developing Stroke Education Programs for West Michigan Asian Communities
Authors: Antonio Aileen A. , Anderson Taylor , Ngo Vincent , Park Sojung , Woolner Susan , Farooq Muhammad , Santos Ronel , Gorelick Philip
Published: February 2024

BACKGROUND:

Asians in the United States, facing health care disparities, have increased stroke risk. Multiple subgroups, with distinct cultures and languages, add complexity to caring for Asian American (AsA) communities. We developed a tailored stroke education program for underserved West Michigan AsA communities. Methodology, lessons learned, and diversity, equity, and inclusion insights are described.

METHODS:

Neurology residents and faculty, in collaboration with trained community-specific navigators, developed culturally resonant stroke education that was tailored to meet the needs of specific self-identified West Michigan AsA communities. Educational and debriefing sessions were delivered over 6 months, following the Plan-Do-Study-Act model, to elucidate diversity, equity, and inclusion insights and improve materials and delivery methods.

RESULTS:

Eighty-six non-English-speaking participants from 5 self-identified AsA communities (Burmese, Buddhist Vietnamese, Catholic Vietnamese, Chinese, and Nepali) attended educational stroke sessions. The average age of attendees was 57.6±13.2 years; most were females (70%). Diversity, equity, and inclusion insights included identification of Asian cultural beliefs about acute stroke treatment (eg, bloodletting), investigator insights (eg, need for kitchen-table programs), systemic barriers (eg, language), and mitigation strategies.

CONCLUSIONS:

Institutions should consider the integration of equity-focused, trainee-influenced quality improvement projects, such as this culturally resonant stroke educational program for AsA, to enhance stroke care in these vulnerable communities.