Citations

Introduction: Mechanical thrombectomy (MT) is a primary treatment for acute ischemic stroke due to large vessel occlusions. While effective, 20-40% of patients experience hemorrhagic transformation (HT), and around 50% fail to achieve favorable functional outcomes. Transcranial Doppler (TCD) is a non-invasive and cost-effective method for real-time monitoring of hemodynamic status following MT. However, the prognostic value of TCD parameters in predicting HT and poor functional outcome is unclear. We performed a systematic review and meta-analysis of 4 TCD parameters (mean flow velocity (MFV), MFV index, peak systolic velocity (PSV), and pulsatility index (PI) in patients with and without HT and favorable vs poor functional recovery (modified Rankin Scale (mRS) 0-2 vs 3-6). Methods: PubMed, Embase, and Scopus were searched on July 25, 2024 to identify observational studies in which TCD parameters were measured within 48 hours from successful MT (Thrombolysis in Cerebral Infarction 2b–3) of anterior circulation. Risk of bias assessment was performed using a standardized tool tailored for TCD studies. The standardized mean difference (Hedges’ g) with 95% CI and risk ratios (RRs) with 95% CI were calculated using random-effects models. The review was prospectively registered on PROSPERO (registration number CRD42024575381). Results: Eleven studies met inclusion criteria. No study had high risk of bias. MFV and MFV index were higher in patients with HT+ compared with HT- (Hedges' g = 0.42 and 0.54, p = 0.015 and 0.005, respectively). Patients with MFV index ≥1.3 showed a higher risk of all HT (RR = 2.01, 95% CI = 1.27–3.17, p = 0.003), symptomatic HT (RR, 4.68; 95% CI,1.49–14.65, p=0.008), and poor functional recovery at 90 days (RR, 1.66; 95% CI,1.32–2.08, p<0.001), respectively. There was no difference in mean PSV (p=0.1) and PI (p=0.3) among groups with and without HT. Conclusion: Our study highlights the prognostic value of TCD parameters, particularly MFV index, in predicting HT, symptomatic HT, and poor functional recovery after successful MT in the anterior circulation. Our findings were limited by low number of studies. Large-scale and multi-center studies are needed to confirm these findings and validate the MFV index as a reliable predictor to improve post-thrombectomy care.

Background: High adherence to the Mediterranean Diet (MeDi) was associated with better cognitive performance and decreased memory decline among Hispanic or Latino adults. Objective: Investigate if higher adherence to the MeDi improves white matter (WM) integrity among Hispanic/Latino adults and if this effect is mediated by cardiovascular health (CVH). Methods: We included 2,774 participants from the Study of Latinos-Investigation of Neurocognitive Aging-MRI Ancillary Study. Participants completed 24-hour dietary recalls at baseline (2008-2011) which were used to calculate a MeDi score (MeDiS, range 0-9). Brain MRI and diffusion tensor images were collected between 2018 and 2022 on a 3T MRI scanner using a standardized protocol. WM integrity was ascertained using WM hyperintensity (WMH) volume and fractional anisotropy (FA). WMH volumes were residualized for total cranial volume and Ln-transformed prior to analysis. The association of MRI outcomes with MeDiS and its components was investigated using weighted linear regression analysis with complex survey design adjusting for age, sex, sociodemographic characteristics. Cardiovascular health was assessed using the Life’s Simple 7 (LS7, range 0-14) score. The mediating effect of LS7 on the primary outcome was reported as Average Causal Mediation Effects (ACME) and Average Direct Effects (ADE). Statistical significance was set at p<0.05. Results: Mean age (95% CI) at MRI scan was 64.0 (63.4 to 65.2) and 44% were males. Mean MeDiS was 5.01 (4.89 to 5.12) and LS7 was 7.1 (7.0 to 7.3). In our fully adjusted model, increasing MeDi adherence was associated with decreased LnWMH volume (β=-0.07, 95% CI -0.10 to -0.03) and increased FA (β=0.002, 95% CI 0.001 to 0.003). Increasing LS7 scores partially mediated the relationship between MeDiS and WMHs (ACME=-0.01, ADE=-0.08, p<0.05, percent mediation=9%) and between MeDiS and FA (ACME=0.0001, ADE=0.002, p<0.01, percent mediated=8%). Among the different MeDi components, consumption of whole grains and fish above sex-specific energy adjusted energy median intake predicted lower WMH volume and increase FA (p<0.05 for both). Conclusions: Among diverse Hispanic/Latino adults, high MeDi adherence was associated with preserved WM integrity. This association was partially mediated by CVH. This suggests that the beneficial effect of MeDi on brain health is not fully explained by vascular risk factors. A culturally tailored MeDi may preserve brain health among Hispanic/Latino adults.

Introduction: Embolic Stroke of Undetermined Source (ESUS) represents about 25% of ischemic strokes, with patent foramen ovale (PFO) involved in roughly 25% of those cases. Recent studies (REDUCE, CLOSE, RESPECT) indicate that PFO closure may benefit select patients. Accurate PFO diagnosis is crucial for treatment decisions but current methods, such as transcranial Doppler (TCD) with bubble study, transthoracic echocardiography with bubble study (TTE), transesophageal echocardiography (TEE), and cardiac computed tomography (CT), vary in accuracy. This study aims to assess the diagnostic performance of TCD compared to TTE, TEE, and cardiac CT, to determine the most reliable modality for detecting PFO in patients with ESUS. Methods: We conducted a retrospective analysis of ESUS patients aged 18 and older referred to our vascular lab between July 2023 and September 2024. Each patient underwent at least two PFO detection methods: TCD with bubble study, TTE with bubble study, TEE, and cardiac CT. PFO presence was confirmed if identified by at least two detection methods. Patients with extracardiac shunts were excluded. Sensitivity, specificity, and overall test performance were evaluated using the Area Under the Curve (AUC) of a Receiver Operating Characteristic (ROC) curve, with higher AUC values indicating better performance. Differences in AUCs were assessed using DeLong’s test. Statistical analysis was performed using Analyse-it for Microsoft Excel (version 2.30). Results: Of 187 enrolled patients, 63 (33.7%) had evidence of right-to-left shunt. The mean age of the cohort was 63 ± 18 years, with 51% being male. PFO was confirmed in 36 patients. Sensitivity was highest for TCD (93.1%), followed by TTE (87.1%), TEE (86.7%), and cardiac CT (42.9%). Specificity was highest for cardiac CT (87.5%), followed by TTE (84%), TCD (59.1%), and TEE (47.1%). The AUC was highest for TTE (AUC: 0.85, 95% CI: 0.76–0.95), followed by TCD (AUC: 0.75, 95% CI: 0.64–0.87), TEE (AUC: 0.66, 95% CI: 0.50–0.81), and cardiac CT (AUC: 0.65, 95% CI: 0.42–0.88). No statistically significant differences in diagnostic performance across pairwise comparisons were found (p > 0.05). Conclusion: TCD with bubble study is highly sensitive for screening right-to-left shunt, while cardiac CT is highly specific for detecting PFO in ESUS patients. Further studies with larger sample sizes are needed to confirm these findings and refine diagnostic strategies.

AbstractIntroductionClinicopathological correlations differ by sex in Lewy body dementia (LBD). However, previous studies have focused on pathological staging systems that place less emphasis on regional pathologies.MethodsWe included 357 people (131 female, 226 male) with a high likelihood of LBD based on pathology from the Brain Bank for Neurodegenerative (Jacksonville, FL). Sex differences for regional Lewy body, senile plaque, and neurofibrillary tangle counts and their associations with clinical LBD diagnosis were assessed.ResultsFemales were less likely to have a clinical LBD diagnosis; they had more Lewy bodies, neurofibrillary tangles, and senile plaques in various regions than males (all p’s < 0.05). A higher likelihood of clinical LBD diagnosis was associated with more middle frontal, cingulate, and entorhinal Lewy body pathology, and more so for males than for females (all p’s < 0.045).DiscussionSex differences for clinicopathological correlations in LBD also occur at the regional pathology level. Females have a higher frequency of clinical misdiagnosis than males.Highlights Females have a higher risk of clinical underdiagnosis for Lewy body dementia (LBD) than males. Regional pathology counts differ by sex for people with a high likelihood of LBD. Regional pathology association with clinical LBD diagnosis differs by sex. Regional Lewy body counts have a stronger association with LBD phenotype for males.

Aims The current American Joint Committee on Cancer (AJCC) staging manual and the College of American Pathologists (CAP) colorectal carcinoma (CRC) protocol specify use of a four‐tiered grading system (i.e. grades 1–4; well‐differentiated–undifferentiated) for CRC, based on percentage of gland formation. The World Health Organization (WHO) 5th edition grades CRC into low‐grade (well‐ and moderately differentiated) and high‐grade (poorly and undifferentiated), based on the least differentiated component. We studied interobserver agreement and practice patterns among pathologists when grading CRC by these two grading systems. Methods and results Five gastrointestinal pathologists reviewed 100 scanned CRC slides and graded the tumour on each slide, per provided criteria in (a) WHO 5th edition book, (b) AJCC manual/CAP CRC protocol and (c) their clinical practice. A questionnaire for grading selected CRC subtypes was also provided. Statistical analysis was performed using Pearson's χ 2 test and Fleiss multi‐rater kappa analyses. Overall, agreement among the five reviewers when grading via WHO and AJCC criteria for low‐grade and high‐grade CRC was moderate ( κ = 0.568, P < 0.001) and good ( κ = 0.611, P < 0.001), respectively. All reviewers graded significantly more tumours as high‐grade when using WHO (median = 46) versus AJCC/CAP criteria (median = 20). Conclusions Interobserver agreement was higher using the AJCC grading criteria as a two‐tiered system. Significantly more tumours were called high‐grade using the WHO criteria. This raises concerns regarding upgrading tumours, as well as potential differences in grading tumours among pathologists worldwide, based on regional preferred grading systems. Synchronisation of these two grading systems is necessary for uniform grading of CRCs throughout institutions.

614 Background: Liver transplantation (LT) offers a 5-year survival exceeding 70% for selected patients with hepatocellular carcinoma (HCC). Immune checkpoint inhibitors (ICIs) may be used to downstage or bridge to transplantation. This study aims to evaluate the safety of ICIs prior to LT. Methods: Multicenter retrospective study, involving 9 centers, included adults who received ICIs and, subsequent LT, between 2019 and 2023. The ICI cohort was matched by age, sex, liver diseases and transplant date (1:3) with a similar cohort of HCC transplanted patients that did not receive ICIs. Results: The ICI cohort included 45 patients (Table part 1). The most common underlying liver diseases were viral. 15.5% of patients had macrovascular invasion and, 62.2% multifocal disease. The most commonly used ICI was nivolumab (75.6%), followed by atezolizumab-bevacizumab (17.8%). The median follow up was 32.5 months (17.4 - 47.6). The median ICI duration was 147 days (129.5-276.5), with a median interval of 58 days (22–193) between the last ICI dose and LT. There were 8 (17.8%) cases of graft rejection, 2 steroid-resistant leading to 1 graft failure. There were 4 (8%) HCC recurrences. During follow-up there were 6 deaths, 2 related to HCC recurrence and 4 non liver related. When compared with 135 non-ICI cohort patients, there were no differences within the groups (Table part 2). Importantly, we found no significant differences in crude rejection rates (p=0.5). Conclusions: Our study suggest that ICI treatment prior to LT is safe. ICI rejection primarily occurs in the acute post-transplant period (within 3 months), with a low risk of death due to graft failure. Further clinical trials are needed. Part 1: ICI cohort descriptive analysis. N (%); Median (IQR); Part 2: Comparison between cohorts. N (%); Mean (SD). (part 1) ICI-cohort n=45 General data Male 38 (84.4) Age 61.2 (7.6) Etiology of liver diseases Hepatitis C 17 (37.8)Hepatitis B 6 (13.3)MASLD 6 (13.3)Viral +Alcohol 5 (11.1)Alcohol 3 (6.7)Autoimmune 3 (6.7)Other 3 (6.7)Combined viral 2 (4.4) Largest tumor (mm) 39 (22) Macrovascular invasion 7 (15.5) Multifocal 28 (62.2) Locoregional therapy 36 (80.0) Number of locoregional therapies 2 (2) Immunotherapy Nivolumab 34 (75.6) Atezolizumab/bevacizumab 8 (17.8) Pembrolizumab 1 (2.2) Nivolumab+pembrolizumab 1 (2.2) PD1 inhibitor clinical trial 1 (2.2) Days of ICI treatment 147 (203) Radiological tumor response ICI No 17 (37.8) Transplant Deceased donor 43 (95.6) Washout period (days) 58 (171) Induction therapy (anti-thymoglobulin) 8 (17.8) Outcomes Rejection Biopsy proven 8 (17.8) 8 (100) Time to rejection (days) 43 (102) Graft failure Rejection 2 (4.4)1 (2.2) HCC recurrence 4 (8) Deaths 6 (13.3) Follow up Since transplant (months) 32.5 (30.2) (part 2) ICI-cohort (n=45) Non-ICI cohort (n= 135) P Post transplant rejection rate 8 (17.8) 32 (23.7) 0.53 Time to rejection (days) 180.1 (SD 218) 62.2 (SD 62.8) 0.25 Overall deaths 6 (13.3) 10 (7.4) 0.36

766 Background: BASECAMP-1 (NCT04981119) is a pre-screening study to identify patients with tumor-associated human leukocyte antigen (HLA)-A*02 loss of heterozygosity (LOH) for interventional studies, such as EVEREST-2 (NCT06051695), a phase 1/2 study of logic-gated chimeric antigen receptor T-cell (CAR T) therapy for MSLN-expressing cancers. MSLN is a cell surface protein expressed in several cancer types, including mesothelioma (MESO), colorectal (CRC), non-small cell lung (NSCLC), ovarian (OVCA), and pancreatic (PANC) cancer, which can be associated with poor prognosis (1). Longitudinal clinical, genomic, and biomarker data were collected from patients enrolled in BASECAMP-1, providing a large dataset for translational discovery and propensity scoring. The aim of this analysis was to determine whether MSLN expression measured by RNAseq and IHC are correlated among patients with solid tumors. Methods: In BASECAMP-1, tumor tissue from patients with germline heterozygous HLA-A*02 is tested for HLA-A*02 LOH using an investigational next generation sequencing device codeveloped with Tempus Labs (Lozac'hmeur, et al. NPJ Precis Oncol. 2024) that detects somatic alterations, including HLA LOH, and generates RNAseq data (eg, MSLN expression). Gene-level transcripts per million read (TPM) values were determined and the log2 TPM +1 was displayed in a scatter plot (the mean and standard deviation [SD] are provided in the Table). Patients with HLA-A*02 LOH also submit tissue for IHC testing for exploratory biomarkers (eg, MSLN expression using anti-MSLN clone 5B2). Statistical significance was determined with ANOVA or t-tests. Results: As of June 1, 2024, 314 patients had been screened for BASECAMP-1 and had RNAseq results; 34 patients also had MSLN IHC results. MSLN expression by RNAseq was consistently higher in patients with PANC or OVCA vs CRC or NSCLC ( P <0.001). MSLN expression by RNAseq and IHC were correlated overall ( P <0.001), particularly among patients with PANC and OVCA. Among the 8 patients with OVCA or PANC who were IHC+ for MSLN, only 1 had an RNAseq value below 6 log2 TPM+1; this patient had mesonephric-like ovarian adenocarcinoma, which may account for the low value. The one MESO sample with both RNAseq and IHC available was IHC+ and had a high RNAseq value. Conclusions: This analysis demonstrated high correlation between RNAseq and IHC MSLN expression in tumor tissue. 1. Faust, et al. Cancers. 2022. Clinical trial information: NCT04981119 . MSLN expression by RNASeq by tumor type and IHC status. Tumor Overall (N=314) IHC data available (n=34) MSLN Positive MSLN Negative n Mean TPM a (SD) n Mean TPM a (SD) n Mean TPM a (SD) All 314 5.1 (2.3) 20 6.0 (2.1) 14 2.3 (1.7) adNSCLC 33 3.8 (2.4) 2 4.7 (1.7) 7 1.5 (1.3) sqNSCLC 4 3.1 (1.8) 0 0 MESO 4 4.5 (4.2) 1 5.7 0 CRC 148 4.4 (2.0) 8 5.1 (2.1) 7 3.1 (1.6) PANC 100 6.1 (1.8) 3 7.8 (0.6) 0 OVCA 25 7.2 (2.1) 5 6.6 (2.8) 0 a MSLN log2 transcripts per million+1. ad, adenocarcinoma; sq, squamous.

TPS788 Background: MSLN is a desirable candidate for targeted therapy given its limited expression in normal tissues and its overexpression in several malignancies, including PANC, mesothelioma, non-small cell lung, and ovarian cancers (TCGA 2022). MSLN-targeted CAR T and T-cell receptor therapies have shown promising clinical activity; however, on-target, off-tumor toxicity, including fatal events, have occurred (1-3). Autologous logic-gated Tmod CAR T therapies address the challenges of on-target, off-tumor toxicity by combining 2 CARs: activating and blocking receptors. The activator recognizes a tumor-associated antigen present on the surface of both tumor and normal cells; the blocker prevents CAR T activity when it binds HLA-A*02, which is present in normal cells and often lost in tumor cells. Thus, in patients with tumor-associated HLA-A*02 LOH, the blocker prevents on-target, off-tumor toxicity on normal cells due to retained HLA-A*02 expression (4). HLA-A*02 LOH is observed in various solid tumors, including ~20% of PANC (5). Two autologous CAR T therapies are currently under investigation: A2B530, targeting carcinoembryonic antigen, in the EVEREST-1 trial, and A2B694, targeting MSLN, in the EVEREST-2 trial, described herein. A2B694 may provide a therapeutic window to treat patients with PANC and other MSLN-expressing solid tumors exhibiting HLA-A*02 LOH due to its unique discriminatory mechanism. Methods: EVEREST-2 (NCT06051695) is a first-in-human, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B694 for recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression, including PANC. Eligible patients must have exhausted options of potentially curative therapy and have recurrent disease. Enrollment to EVEREST-2 occurs through the prescreening study BASECAMP-1 (NCT04981119), in which patients with tumor-associated HLA-A*02 LOH are identified via next-generation sequencing (Tempus AI, Inc) and leukapheresis product is collected. A2B694 is manufactured from cryopreserved T cells when clinically appropriate for patients. The primary objective of phase 1 is to evaluate the safety and tolerability of A2B694 and identify the recommended phase 2 dose (RP2D). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B694. Phase 2 will assess the primary endpoint overall response rate per RECIST v1.1 and secondary endpoints progression-free survival and overall survival. The first patient was dosed on April 24, 2024 and dose escalation is ongoing. 1. Beatty, et al. Gastroenterology . 2018. 2. Haas, et al. Mol Ther . 2023. 3. Hong, et al. ESMO 2021. Abstr 9590. 4. Hamburger, et al. Mol Immunol . 2020. 5. Hecht, et al. J Clin Oncol . 2022. Clinical trial information: NCT06051695 .