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484 Background: The histopathological growth patterns (HGPs) of liver metastasis reflect the complicated and varied interactions between tumor cells and the host microenvironment. We studied HGPs of gastric cancer liver metastasis (GCLM) and sought to predict them using radiomic and clinical variables. Methods: Hepatectomy was performed in 62 patients with GCLM at our university hospital between 2011 and 2021. HGPs were evaluated according to international consensus guidelines, and were classified as either desmoplastic HGP (dHGP) or non-dHGP. CD4, CD8, VEGF and CD31 were analyzed by immunohistochemistry. Eight hundred and fifty-one radiomics features were extracted from CT portal venous phase images and the optimal radiomics signature was determined by univariate analysis and LASSO regression. Multivariable regression analyses and ROC curves were used to assess the predictive performance of HGPs with a radiomic and clinical combined model. Results: Among 62 patients, 14 were categorized as dHGP, and 48 as non-dHGP. Non-dHGP vs. d-HGP was associated with higher tumor N stage and CEA level, and with decreased CD8 + T cells, and lower VEGF and CD31 expression. HGP status was independently associated with patient cancer-specific survival (CSS) (P＜0.05) multivariately.Analysis of percent relative contribution revealed that HGP ranked first for CSS (35.9%), ahead of T (28.9%) and N (28.9%) stage. A model with combined radiomic and clinical features demonstrated robust performance with area under the curve (AUC) values of 0.993 and 0.933 in the training and validation sets, respectively. Conclusions: Non-invasive determination of radiomic and clinical features was shown to predict HGPs types. Compared to dHGP, GCLM with non-dHGP exhibited significantly lower immune cell infiltration and decreased angiogenesis. Among features examined in GCLM, HGP was the most robust for prognostication. Univariate and multivariate analysis of prognostic factors for cancer-specific survival. Characteristics Univariate analysis Multivariate rergression analysis HR (95%CI) P HR (95%CI) P Gender ( Women vs Men ) 1.13(0.61-2.09) 0.71 Age ( >60years vs ≤60years) 1.08(0.60-1.70) 0.98 HGP ( non-desmoplastic HGP vs desmoplastic HGP ) 3.63(1.78-7.41) 0.00 3.48(1.37-8.88) 0.01 T stage ( T3-T4 vs T1-T2 ) 2.03(1.08-3.80) 0.03 2.29(1.15-4.58) 0.02 N stage ( N1-N3 vs N0 ) 3.46(1.66-7.23) 0.00 2.54(1.17-5.56) 0.02 CEA ( >5ng/ml vs ≤5ng/ml ) 2.37(1.25-4.48) 0.01 1.56(0.70-3.48) 0.27

483 Background: Heterogeneity exists in recurrence and survival among patients with intestinal-type gastric cancer (IGC). Nucleotyping is the alterations in chromatin organization. We sought to identify the prognostic utility of nucleotyping, tumor stroma ratio (TSR) and DNA ploidy in these patients. Methods: Radical resection of gastric carcinoma (> 15 LNs removed) was performed in 283 patients (stage I, n=73; stage II, n=102; stage III, n=108) at our university hospital between 2010 and 2018. Automated image cytometry tools were used to quantitatively measure nucleotyping, TSR and DNA ploidy. Cutpoints of nucleotyping and TSR were 0.044 and 50%, respectively. Associations of these features with clinicopathological characteristics, time-to-recurrence (TTR) and cancer specific survival (CSS) were analyzed by univariate and multivariate analysis. Results: Among 283 patients, chromatin heterogeneity, high TSR and non-diploid were significantly associated with larger tumor size, higher T and N stage, and poorer TTR and CSS at 5 years. In a Cox multivariable analysis, nucleotyping and TSR were independently associated with TTR and CSS (P＜0.05) (Table). The top three contributors to TTR were N stage (33.9%), nucleotying (29.7%) and TSR (25.5%). The top three contributors to CSS were N stage (35.6%), nucleotying (29.7%) and TSR (18.0%). As a combined variable, the percent relative contribution of nucleotyping and TSR ranked first for TTR and CSS (56.0%, 50.0%), ahead of N stage (33.4%, 34.6%) and TILs (8.4%, 10.6%). Conclusions: Nucleotyping and TSR were each significantly and independently associated with TTR and CSS, and their combined variable was more strongly prognostic than either alone. Cox multivariable analysis of TTR and CSS. Features TTR HR (95%CI) TTR P value CSS HR (95%CI) CSS P value Tumor size (>3cm vs ≤3cm) 1.10 (0.48-2.54) 0.83 0.77 (0.35-1.70) 0.56 T stage (T3-T4 vs T1-T2) 1.07 (0.46-2.49) 0.87 1.41 (0.53-3.76) 0.49 N stage (N2N3 vs N0N1) 2.84 (1.39-5.78) <0.01 7.69 (3.37-17.55) <0.01 Adjuvant Therapy (with vs without) 1.32 (0.72-2.40) 0.37 0.85 (0.48-1.52) 0.59 TB (high vs low) 1.29 (0.62-2.69) 0.50 1.61 (0.85-3.07) 0.15 TILs（low vs high） 1.73 (0.96-3.13) 0.07 1.90 (1.06-3.40) 0.03 Nucleotyping (Chromatin heterogeneous vs Chromatin homogeneous) 2.19 (1.21-3.99) 0.01 3.44 (1.96-6.03) <0.01 TSR (high vs low) 2.12 (1.16-3.82) 0.01 2.51 (1.43-4.41) <0.01 DNA ploidy (Non-diploid vs Diploid) 1.20 (0.55-2.63) 0.65 0.98 (0.44-2.15) 0.95 1 TTR, time-to-recurrence; 2 CSS, cancer specific survival.

Abstract Background: The trajectory of metastatic castration-sensitive prostate cancer varies based on disease presentation and biology. While proteomic profiling studies of primary prostate tissue have linked protein expression with metastatic progression and prognosis, few studies have explored biological changes after treatment and their associations with response. Therefore, we conducted proteomic profiling of patients with oligometastatic castration-sensitive prostate cancer (omCSPC) treated with stereotactic ablative radiotherapy (SABR) or observation in the ORIOLE phase 2 randomized clinical trial (RCT). Methods Plasma from omCSPC patients in the ORIOLE trial was collected at baseline (day 1), day 90, and day 180. Protein abundance was quantified using the Olink Explore Assay. Differential expression from baseline to day 90 or 180 in each treatment arm was analyzed using a 2-sided t-test with Benjamini-Hochberg correction. Changes in protein expression at day 90 and 180 were compared with a Pearson correlation. Pathway enrichment was performed via gene set enrichment analysis (GSEA) using Reactome, KEGG, and Hallmark gene sets. Associations with progression-free survival (PFS) were analyzed using Kaplan-Meier and log-rank tests. Results In total, 1,472 proteins were assayed across 130 samples from 46 patients over 3 time points. Significant changes in expression post-SABR were noted at day 90 and 180 compared to baseline (using adjusted p-value cutoff of 0.05). At day 90, four proteins (FCRL1, CD22, TCL1A, FCER2) were downregulated; at day 180, only FCRL1, a Fc receptor-like gene family preferentially expressed in B cells, remained downregulated. No significant expression changes were found in the observation arm. Differential expression of proteins during follow-up were associated with PFS. In particular, LTO1, a maturation factor of ABCE1 important for ribosomal biogenesis and translation, was overexpressed at both day 90 and 180 post-SABR, and overexpression was associated with improved PFS at day 90 (median 24.5 mo vs 6 mo; p=0.017) and day 180 (median 33 mo vs 6 mo; p=0.043). These associations were absent in the observation arm. For proteins differentially expressed in the SABR arm at day 90, several signaling pathways were significantly enriched for patients with prolonged PFS, including positive enrichment of unfolded protein response (UPR) (p=0.008) and IL-4/IL-13 (p=0.009). At 180 days, several pathways were enriched for patients with prolonged PFS including negative enrichment of CTLA4 inhibitory signaling (p=0.005) and CD28 co-stimulation (p=0.008). Conclusion Proteomic analysis in omCSPC patients from the ORIOLE trial reveals significant expression changes at days 90 and 180 after SABR. B-cell signaling proteins were selectively downregulated in the SABR arm, and pathways associated with protein translation and immune response were enriched post-SABR for patients with prolonged PFS. Further research will explore connections to genomic and transcriptomic changes, with additional validation needed. Citation Format: Jarey H. Wang, Amol Shetty, Yang Song, Noura Radwan, Soha Bazyar, Xiaolei Shi, Theodore L. DeWeese, Daniel Y. Song, Ryan M. Phillips, Matthew P. Deek, Philip Sutera, Ana P. Kiess, Phuoc T. Tran. Proteomic profiling of oligometastatic castration-sensitive prostate cancer treated with stereotactic ablative radiotherapy. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B031.

Background Resilience refers to the ability to adapt or recover from stress. There is increasing appreciation that it plays an important role in wholistic patient-centered care and may affect patient outcomes, including those of orthopaedic surgery. Despite being a focus of the current orthopaedic evidence, there is no strong understanding yet of whether resilience is a stable patient quality or a dynamic one that may be modified perioperatively to improve patient-reported outcome scores. Questions/purposes (1) Does resilience change postoperatively? (2) How do outcome measures change postoperatively in relation to resilience grouping? (3) For patients who do have resilience instability (change in resilience of ≥ 1 SD between any two follow-up points), how were patient-level factors, surgical characteristics, and outcome measures associated with instability? Methods In this single-surgeon, retrospective, comparative study, we identified all patients who underwent shoulder surgery between March 2021 and March 2023 from the medical records of one US military teaching hospital, resulting in 144 initial patients. Data on resilience (measured by the Brief Resilience Scale) and outcomes (assessed using the Numeric Rating Scale [NRS] and the Single Assessment Numeric Evaluation [SANE]) were collected for all patients and maintained in a longitudinal outcomes score database. Patients younger than 18 years of age (1% [1 of 144]) who underwent surgery for fracture, acute tendon rupture (8% [11 of 144]), or revision surgery (3% [4 of 144]); had concomitant shoulder conditions (such as, instability or rotator cuff tear) (1% [2 of 144]); or had incomplete follow-up data (4% [5 of 144]) were excluded, leaving 84% (121 of 144) of the original sample size for analysis. Among the patients, 12% (15 of 121) were women, the mean age was 41 ± 15 years, and the most common indication for surgery was instability (40% [48 of 121]) followed by rotator cuff repair (29% [35 of 121]). Based on their preoperative Brief Resilience Scale and its deviation from the mean, patients were stratified into low (> 1 SD below mean), intermediate (within 1 SD above and below mean), and high (> 1 SD above mean) resilience groups. Preoperatively, 19% (23 of 121) of patients were classified as low resilience, 62% (75 of 121) as intermediate resilience, and 19% (23 of 121) as high resilience. The mean ± SD preoperative Brief Resilience Scale score was 25 ± 4. The Brief Resilience Scale is a six-item scale with a calculated summary score ranging from 6 to 30. A higher score is suggestive of greater perceived resilience. There were no differences in the preoperative Brief Resilience Scale score with regard to age, gender, type of surgery performed, or outcome measures. Patient resilience was followed during the postoperative period for a minimum of 6 months, and instability in the scale was evaluated. Instability in resilience was defined as change in Brief Resilience Scale score by > 1 SD from one follow-up time point to another. Perioperative NRS and SANE outcomes, in addition to demographic data, were utilized to evaluate the relationship between resilience and patient-level factors. Results Brief Resilience Scale groups across all time points remained consistent with no change in grouping or crossover in groups except for patients with low resilience who had an increase in mean ± SD Brief Resilience Scale score by the final follow-up (18 ± 3 versus 20 ± 4; p < 0.05). Regardless of resilience group, there was a decrease in mean ± SD NRS (4.4 ± 2.2 versus 2.4 ± 2.3; p < 0.001) and an improvement in mean ± SD SANE (46 ± 19 versus 69 ± 21; p < 0.001) scores during the postoperative period. At the 1- to 2-month follow-up and the 6- to 10-month follow-up visits, patients with high resilience were more likely to have lower NRS scores than patients with intermediate resilience (1.8 ± 1.0 versus 3.8 ± 2.3; p = 0.003) and low resilience (1.5 ± 1.8 versus 3.3 ± 2.4; p < 0.001), respectively. No relationship was observed between resilience groups and SANE scores, surgical category, and percentage of patients meeting the minimum clinically important difference (MCID) of the NRS or the SANE. Regarding resilience instability, 46% (56 of 121) of patients were categorized as having a Brief Resilience Scale change of ≥ 1 SD from baseline during the postoperative period. Gender (r = 0.03; p = 0.21), age (p = 0.81), and surgical category (r = 0.01; p = 0.88) were not associated with the likelihood of resilience instability. Individuals whose resilience increased had a lower starting Brief Resilience Scale score than those whose resilience stayed the same (22 ± 4 versus 25 ± 4, respectively; p < 0.001) or those whose resilience decreased (22 ± 4 versus 26 ± 3, respectively; p < 0.001). Conclusion When evaluated by resilience group, the trait appears static; however, at the individual level, resilience appears dynamic and complex. Patients with high resilience may have less postoperative pain. Identification of patients with low resilience may indicate patients who experience more dynamic change in this psychometric property. Level of Evidence Level III, therapeutic study.

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

Abstract Background Perry syndrome (PS) is a rare and fatal hereditary autosomal dominant neurodegenerative disorder caused by mutations in dynactin ( DCTN1 ). PS brains accumulate inclusions positive for ubiquitin, transactive‐response DNA‐binding protein of 43 kDa (TDP‐43), and to a lesser extent dynactin. Objectives Little is known regarding the contributions of TDP‐43, an RNA binding protein that represses cryptic exon inclusion, in PS. Therefore, we sought to identify the degree of TDP‐43 dysfunction in two regions of PS brains. Methods We evaluated the levels of insoluble pTDP‐43 and TDP‐43‐regulated cryptic RNAs and protein in the caudate nucleus and substantia nigra of 7 PS cases, 12 cases of frontotemporal lobar degeneration (FTLD) with TDP‐43 pathology, and 11 cognitively healthy controls without TDP‐43 pathology. Results Insoluble pTDP‐43 protein levels were detected in PS brains to a similar extent in the caudate nucleus and substantia nigra but lower than those in FTLD brains. The caudate nucleus of PS showed accumulation of eight TDP‐43‐regulated cryptic RNAs ( ACTL6B , CAMK2B , STMN2 , UNC13A , KCNQ2 , ATG4B , GPSM2 , and HDGFL2 ) and cryptic protein (HDGFL2) characteristic of FTLD. Conversely, only one cryptic target, UNC13A , reached significance in the substantia nigra despite similar pTDP‐43 levels. Conclusion We detected TDP‐43 cryptic RNAs and protein in PS caudate nucleus. Given the importance of cryptic exon biology in the development of biomarkers, and the identification of novel targets for therapeutic intervention, it is imperative we understand the consequences of TDP‐43 dysfunction across different brain regions and determine the targets that are specific and common to TDP‐43 proteinopathies. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

ImportanceAtrial fibrillation (AF) is the most common, chronic, cardiac arrythmia in older US adults. It is not known whether AF is independently associated with increased risk of retinal stroke (central retinal artery occlusion), a subtype of ischemic stroke that causes severely disabling visual loss in most cases and is a harbinger of further vascular events.ObjectiveTo determine whether there is an association between AF and retinal stroke.Design, Setting, and ParticipantsThis retrospective cohort study was performed between July 2023 and May 2024 using computerized inpatient, outpatient, emergency department, and skilled nursing facility claims files for a 5% sample of US fee-for-service Medicare beneficiaries aged 66 years and older between 2000 and 2020. Follow-up ended at death, conclusion of fee-for-service Medicare coverage, end of the study period, or loss to follow-up of 85% of the study cohort.ExposureAF, based on validated International Classification of Diseases, Ninth Revision, Clinical Modification and International Statistical Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes.Main Outcomes and MeasuresThe primary end point was incident retinal stroke in the primary diagnostic position of a single claim in any venue of care. Secondary end points included retinal stroke in any position of a single claim, 1 positive control end point (cerebral ischemic stroke), and 4 negative control end points (central retinal vein occlusion, urinary tract infection, humeral fracture, and cataract). Unadjusted and adjusted hazard ratios (HRs) and rate differences were computed across matched and overlap-weighted cohorts with and without AF (defined as 1 inpatient claim or 2 outpatient claims within a 365-day period).ResultsIn total, 1 090 144 patients (591 400 female [54.3%]; mean [SD] age, 76.92 [7.09] years) were included in the study; 545 072 patients had AF and 545 072 were matched controls. The median (IQR) follow-up was 45 (18 to 90) months. In total, 1333 patients with AF (rate, 0.55 per 1000 person-years) and 1082 AF-free matched controls (rate, 0.50 per 1000 person-years) experienced retinal stroke. The cause-specific, adjusted HR of retinal stroke after overlap weighting was 1.14 (95% CI, 1.02 to 1.28; adjusted rate difference, 0.05 [95% CI, −0.01 to 0.11]). AF was associated with cerebral ischemic stroke (adjusted HR, 1.73 [95% CI, 1.69 to 1.76]; adjusted rate difference, 10.11 [95% CI, 9.72 to 10.49]). Of 4 prespecified negative control end points, AF was not associated with central retinal vein occlusion but was associated with urinary tract infection, cataract, and humeral fracture.Conclusions and RelevanceIn this cohort study of Medicare beneficiaries aged 66 years and older, AF was independently associated with retinal stroke. The magnitude of the association was small, and a contribution from residual, unmeasured confounding could not be excluded.

AbstractBackgroundIndividuals meeting neuropathological criteria for Alzheimer’s disease (AD) may manifest with atypical clinical syndromes. Past work showed that the neurobiological basis for these differences is related to specific neuronal vulnerabilities for tau pathology. For instance, amnestic cases have a higher burden of neurofibrillary changes in CA1. In contrast, logopenic variant primary progressive aphasia (lvPPA) cases have a higher tau burden in the superior temporal gyrus (STG). Single‐cell technology enables investigations on the molecular basis of differential neuronal vulnerability in AD. Consequently, we delved into the factors that underlie this selective vulnerability by analyzing brain samples from individuals exclusively afflicted with AD but exhibiting diverse clinical manifestations.MethodsnRNA Sequencing using the Chromium Single Cell 3′ (10X Genomics, USA) on nuclei cells extracted from the CA1 sector and posterior STG of postmortem brain tissue of 48 individuals either meeting pathological criteria for AD (A3B3C3; 24 amnestic and eleven lvPPA) and healthy controls (A≤1B≤1C≤1; n = 13) (Table 1, Fig. 1A/B). Bioinformatics analyses were conducted using Cell Ranger and R software. Comparisons between cell subpopulations were conducted with the Wald statistical test, and p‐values < .05 were considered significant.ResultAfter quality control, we recovered more than 250k nuclei with a mean of 2,130 genes per nuclei. Upon cross‐sample alignment and t‐stochastic neighborhood embedding clustering (Fig. 1C), we found 21 excitatory neuronal subpopulations (Exc‐sub) in CA1 and 26 in STG, and 22 and 25 inhibitory neuronal subpopulations (Inh‐sub) in CA1 and STG, respectively; 16 astrocytes subpopulations in both areas and 20 microglia subpopulations in CA1 and 17 in STG (Fig. 2). One STG Exc‐sub, expressing CUX2 and LAMP5 genes showed vulnerability in lvPPA patients. Also, one STG Inh‐sub, expressing the ADARB2 gene, showed vulnerability for all AD patients.ConclusionOur preliminary study identified a vulnerable population of excitatory neurons related to lvPPA. We are conducting validation studies using quantitative pathology to confirm these results. Furthermore, analysis of a higher number of cases is ongoing and will continue to inform on factors associated with neuronal vulnerability.

ABSTRACTBackgroundThe role of Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) is still unclear in patients with STEMI undergoing PCI in the current second‐generation DES era.AimsThis study aimed to evaluate the trends and outcomes of IVUS‐guided PCI in patients with STEMI.MethodsWe used the National Inpatient Sample (NIS) database from 2016 to 2021. The primary endpoint of this study is all‐cause in‐hospital mortality. Secondary endpoints include trends of PCI hospitalizations, trends of mortality, length of stay, and cost of hospitalization.ResultsThere were data for 819,645 hospitalizations for STEMI, of which 91.2% (n = 74,7860) utilized angiography‐guided PCI, 8.4% (n = 68,985) utilized IVUS‐guided PCI and 0.3% (n = 2800) utilized OCT‐guided PCI. In‐hospital mortality for IVUS‐guided PCI was 4.6% (n = 3190) versus 6.0% (n = 44,935) for angiography‐guided PCI with an adjusted OR 0.75 (0.68–0.81, p < 0.001). In‐hospital mortality for OCT‐guided PCI was 3.4% (n = 95) versus 6.0% (n = 44,935) for angiography‐guided PCI with an adjusted OR 0.67 (0.43–1.06, p = 0.09).ConclusionsIVUS/OCT‐guidance was increasingly utilized over the years and was associated with a significantly reduced adjusted odds of in‐hospital mortality. Large‐scale, long‐term randomized data are needed to better ascertain where IVUS/OCT may be best utilized for optimization of PCI for STEMI.

Abstract As the healthcare burden caused by an increasingly aging population rapidly rises, a pressing need exists for innovative geroscience research that can elucidate aging mechanisms and precipitate the development of therapeutic interventions to support healthy aging. The Fifth Annual Midwest Aging Consortium Aging Research symposium, held from April 28 to 30, 2024, was hosted by The Ohio State University in Columbus, Ohio, and featured presentations from investigators across the Midwestern United States. This report summarizes the research presented at the symposium, whose topics included cellular senescence and the aging brain, metabolism and metabolic interventions, nutrition, redox mechanisms and biomarkers, and stress mechanisms. Abstract presentations and short talks highlighted early-stage and young investigators, whereas 2 keynote presentations anchored the symposium. Overall, this symposium showed the robustness of aging research in the Midwest and underscored the advantages of a collaborative approach to geroscience research.