Results Of Trial Research Articles

The abscopal effects of sonodynamic therapy in cancer

AbstractThe abscopal effect is a phenomenon wherein localised therapy on the primary tumour leads to regression of distal metastatic growths. Interestingly, various pre-clinical studies utilising sonodynamic therapy (SDT) have reported significant abscopal effects, however, the mechanism remains largely enigmatic. SDT is an emerging non-invasive cancer treatment that uses focussed ultrasound (FUS) and a sonosensitiser to induce tumour cell death. To expand our understanding of abscopal effects of SDT, we have summarised the preclinical studies that have found SDT-induced abscopal responses across various cancer models, using diverse combination strategies with nanomaterials, microbubbles, chemotherapy, and immune checkpoint inhibitors. Additionally, we shed light on the molecular and immunological mechanisms underpinning SDT-induced primary and metastatic tumour cell death, as well as the role and efficacy of different sonosensitisers. Notably, the observed abscopal effects underscore the need for continued investigation into the SDT-induced ‘vaccine-effect’ as a potential strategy for enhancing systemic anti-tumour immunity and combating metastatic disease. The results of the first SDT human clinical trials are much awaited and are hoped to enable the further evaluation of the safety and efficacy of SDT, paving the way for future studies specifically designed to explore the potential of translating SDT-induced abscopal effects into clinical reality.

Tumor-associated macrophages in bladder cancer: roles and targeted therapeutic strategies

Bladder cancer (BC) is the ninth most common and “expensive” cancer in the world. Despite the availability of various treatment modalities such as chemotherapy, immunotherapy and surgery, the overall survival rate of patients with advanced bladder cancer remains low. As one of the most abundant infiltrating immune cells in bladder cancer, tumor-associated macrophages (TAMs) play an important role in the development of BC and in the standard regimen of intravesical BCG therapy. Targeting TAMs have achieved excellent results in clinical trials for a variety of other cancers, but few studies have been conducted for bladder cancer. Further exploration is still needed to develop TAM-related therapeutic strategies for BC treatment, which are expected to improve the therapeutic efficacy and life quality of patients. This review summarizes the relationship between TAMs in bladder cancer and disease staging, evolution, patient prognosis, and treatment outcome. Several potential TAM targets in BC are also pointed, which may help to inhibit tumor-promoting TAMs and provide new therapeutic approaches for advanced BC.

Abstract 4112952: Developing culturally informed materials to enhance Native Hawaiians' and Pacific Islanders’ participation in clinical trials

Background: Native Hawaiians and Pacific Islanders (NHPI) suffer disproportionately from cardiometabolic disorders and are underrepresented in related clinical trials, limiting our ability to control these disorders for this population. We identified recruitment and retention barriers (complicated clinical language) and facilitators (relationship-building opportunities). Addressing recruitment and retention barriers and facilitators can increase NHPI representation in clinical trials. Goal: To develop culturally informed, educational videos and infographics to improve NHPI trust and attitudes toward research and recruitment and retention in clinical trials. Methods: The videos and infographics are based on focus group data with NHPI past clinical trial participants or staff. The videos focus on recruitment. The infographics focus on recruitment and retention. The videos address the complicated clinical language and hesitancy in disclosing information while leveraging trial outcomes relevant to NHPI health concerns and cultural inclusiveness. The infographics build on the video content. Facilitators include relationship-building opportunities, seeking healthier outcomes for future generations, relationship-building opportunities, and sharing and learning opportunities provided in clinical trials. Results: The Co-Principal Investigators, NHPI clinical trial participants, and NHPI researchers and clinicians contributed to the videos. We created a 5-minute and a 10-minute video. The videos provide 1) an overview of clinical research, 2) considerations for participating in clinical trials, and 3) reasons to participate. Researchers present the first 2 topics, while past participants provide testimonials for the third topic. The 8 infographics include 1) an overview of clinical research, 2) the importance of randomization, 3) research benefits from NHPI participation, 4) the importance of a control group, 5) clinical trial outcomes, 6) individual benefits from research participation, 7) community benefits from research participation, and 8) trust in research. Discussion: We will test the impact of these materials on trust and attitudes towards research and recruitment and retention among NHPI in a randomized clinical trial (RCT). Half of the participants (n=104) will be recruited using traditional strategies and half (n=104) using our novel strategy. Rigorous qualitative (interviews with participants) and quantitative (retention rates) analysis will be conducted.

The Evolving Role of Neoadjuvant Radiation Therapy in Pancreatic Adenocarcinoma

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Surgical resection is the most reliable chance for cure, but high rates of positive margins and local failure persist. Neoadjuvant therapies (NAT), including chemotherapy and radiation therapy (RT), are being explored to improve surgical outcomes, particularly in borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC). This review aims to summarize the current landscape and future directions for neoadjuvant RT (NART) in PDAC. Methods: The review includes a detailed analysis of past and ongoing clinical trials investigating various NART approaches in PDAC, with an emphasis on different RT techniques, fractionation schemes, and their integration into multimodal treatment strategies. Results: Early evidence suggests that NART can improve resection margins and local control. However, recent trials, including the Alliance A021501 and LAP-07 trials, have failed to demonstrate significant survival benefits with the addition of RT to NAT. Nevertheless, nuances in trial design and execution continue to keep the question of NART open. Newer approaches, such as stereotactic magnetic resonance-guided adaptive radiation therapy (SMART), show promise in improving local control and survival, but further phase 3 trials are needed. Conclusions: While NART has shown potential in improving local control in PDAC, its impact on overall survival remains unclear. Ongoing trials, particularly those utilizing advanced techniques like SMART, are critical in defining the role of RT in the neoadjuvant setting for PDAC. Collaboration across multidisciplinary teams is essential to optimize treatment strategies and trial outcomes.

Abstract 4136785: Interpreting Population Mean Treatment Effects in the Kansas City Cardiomyopathy Questionnaire

Introduction: The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a common outcome in heart failure trials. While comparing means between treatment groups improves statistical power, mean effects do not necessarily reflect the clinical benefit experienced by patients. Objectives: To evaluate the relationship between mean KCCQ treatment effects in clinical trials and the proportions of patients experiencing clinically important improvements across a range of heart failure etiologies and interventions. Methods: We performed a patient-level meta-analysis of 11 randomized trials (9,977 patients) to examine the relationship between mean KCCQ Overall Summary Score (OSS) treatment effects and the absolute differences in the proportions of patients experiencing clinically important (≥5 points) and moderate or larger (≥10 points) improvements. Validation was performed in 7 additional trials. Results: Group mean KCCQ-OSS differences were strongly correlated with absolute differences in clinically important changes (Spearman correlations 0.76-0.92). For example, a mean KCCQ-OSS treatment effect of 2.5 points (half of a minimally important difference for an individual patient) was associated with an absolute difference of 6.0% (95% prediction interval [PI] 4.0-8.1) in the proportion of patients improving ≥5 points and 5.0% (95% PI 3.1-7.0) in the proportion improving ≥10 points, corresponding to NNTs of 17 (95% PI 12-25) and 20 (95% PI 14-33), respectively. Similar relationships were observed in the validation studies. Conclusions: Inferences on clinical impact based on population-level mean treatment effects are misleading since even small between group differences may reflect clinically important treatment benefits at the patient level. Clinical trials should explicitly describe the distributions of patient-level KCCQ changes to support clinical interpretation of their results.

Abstract 4140119: Liver Steatosis and Liver Fibrosis Predict Major Adverse Cardiovascular Events in the CLEAR Outcomes Trial

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), and progressive stages accompanied by liver fibrosis (LF), have been associated with liver-related and CV complications in middle-aged patients, although data on the latter is limited. Objectives: We evaluated whether liver steatosis (LS) or LF are associated with CV outcomes in a large clinical trial that included patients at high CV risk who were statin intolerant (SI), and if so, whether bempedoic acid (BA) treatment reduces observed increases in CV risk. Methods: CLEAR Outcomes evaluated the efficacy of BA in 13,970 SI patients randomized to BA (180 mg daily) or placebo and followed for a median of 40.6 months. The primary outcome was a 4-component major adverse CV event (MACE4: nonfatal MI, nonfatal stroke, coronary revascularization, or CV death). This post-hoc analysis used the following non-invasive algorithms to estimate the presence of LS and LF at baseline: Framingham Steatosis Index (FSI), Fibrosis-4 Index (FIB-4) and NAFLD Fibrosis Score (NFS). Continuous variables were reported as mean±SD, categorical variables as proportion. Time-to-event data were analysed using a Cox proportional hazards model. Adjusted hazard ratios (aHR) for every 1 unit increase in score, while holding every other variable constant, and corresponding 95% CI were reported. Results: The mean age of included participants was 66±9 years, 48% were female, mean BMI was 30±5 kg/m 2 , and characteristics were balanced over the treatment arms. Baseline FSI was 0.2±1.5, FIB-4 1.3±0.6 and NFS -0.6±1.2. LS was associated with an increased incidence of MACE4 in the whole study population, as indicated by the aHR of 1.09 (1.06-1.12) for 1 unit of FSI increase. LF was also associated with increased risk of MACE4 in the overall population, aHR 1.19 (1.11-1.28) for 1 unit of FIB-4 increase, and aHR 1.14 (1.10-1.19) for 1 unit of NFS increase. For LS, per 1 unit of FSI increase the aHR for MACE4 was lower in the treatment group: aHR of 1.04 (0.99-1.09) for BA vs 1.14 (1.09-1.18) for placebo, interaction p=0.004. For LF, aHR did not differ between groups and no significant interaction with treatment was observed. Conclusion: Both LS and LF are associated with an increased risk of MACE4. Overall, BA was associated with lower rates of MACE4 across categories of LS and LF (data not shown). A lower risk of LS-associated MACE4 was observed in the BA group. These benefits are less clear regarding the MACE4 risk driven by LF.

Abstract 4144501: Effect of the Cardiac Myosin Activator Omecamtiv Mecarbil on Risk of Ventricular Arrhythmias in Heart Failure with Reduced Ejection Fraction: the GALACTIC-HF Trial

Introduction: The selective cardiac myosin activator, omecamtiv mecarbil (OM), has been shown to benefit individuals with HFrEF but the clinical experience of cardiac myosin activators and incidence of ventricular arrhythmias (VA) is limited. We investigated the prognostic role of VA and the associations between OM, VA occurrence, and outcomes in the GALACTIC-HF trial. Methods: GALACTIC-HF was a placebo-controlled trial testing the efficacy and safety of OM in participants with symptomatic chronic HF and LVEF≤35%. VA were captured based on safety adverse event reporting. Severe HF was defined according to the ESC-HFA criteria. Poisson regression models using restricted cubic splines model were used to assess the association between baseline LVEF and incidence rates of VA. Associations between incident VA and subsequent clinical outcomes were evaluated using time-updated Cox proportional hazard models. Results: Over a median follow-up of 21.8 months, 594 out of the 8,232 individuals randomized in the GALACTIC-HF trial experienced VA, with no statistically significant differences between study arms. Individuals with lower LVEF values were at greater risk of incident VA (per 10% decline: HR 1.37; 95% CI 1.21-1.55; p<0.001) with no significant differences between study arms ( Figure, panel A ). Following VA occurrence, participants were at higher risk of the primary endpoint of CV death or HF events (adj HR 1.67; 95% CI 1.42-1.97; p<0.001) and all-cause mortality (adj HR 2.07; 95% CI 1.77-2.42; p<0.001). The treatment effects of OM on clinical outcomes were consistent in patients not experiencing VA and after VA events. Among the 2,258 participants with severe HF, OM did not affect the risk of VA (adj HR 0.95; 95% CI 0.70-1.29) and this was consistent across the range of LVEF; Figure, panel B . Conclusions: The occurrence of VA among patients with HFrEF is associated with a substantially higher risk of subsequent fatal and non-fatal events. OM did not increase the risk of VA and the beneficial treatment effects were maintained irrespective of VA occurrence. These findings reinforce the safety of OM use among individuals with HFrEF who are at risk of arrhythmic events.

Abstract 4138019: eQTL Analysis of the PAH Biomarker CCN2 Identifies a Novel SNP that Associates with Survival

Background: We recently determined that cellular communication network factor 2 (CCN2) (also known as IGFBP8) levels associate with metrics of severity, and survival, in pulmonary arterial hypertension (PAH). While genetic variants that modify CCN2 gene expression have been described, the variants across the genome that associate with CCN2 protein levels in human circulation remain unknown. Research Question: We sought to identify genetic variants associated with circulating levels of CCN2 and to determine those variants’ relationship with clinical severity and survival. Methods: Serum CCN2 was measured by ELISA in subjects from a national sample repository, the PAH Biobank. A genome wide association study (GWAS) for CCN2 (natural log transformed) was performed in White idiopathic PAH (IPAH) PAH Biobank participants (n = 768) using Illumina OMNI5 genotypes in plink after standard quality control. Subsequent exploration of the SNP of interest was conducted in a separate dataset of 687 White PAH participants (n=360 IPAH, n=313 APAH) linked to genetic and clinical data, including REVEAL 2.0 risk score assessment (divided into low, medium, and high-risk levels) and outcomes (the STRIDE (Sitaxsentan To Relieve Impaired Exercise) trials cohort). Results: In the PAH Biobank, using GWAS, we found CCN2 levels were significantly associated with rs9493157 (p = 2.8 x10 -12 ) ( Figure A ). rs9493157 is reported in the Genotype-Tissue Expression (GTEx) portal to be an eQTL for CCN2 expression in the left ventricle. In the STRIDE cohort, the hazard ratio (HR) for death was 1.33 (99% CI 1.03 to 1.72) for participants with one or more T alleles (p=0.027; ( Figure B )). On multivariate analysis, the HR for death was 1.28 (95% CI 0.99 to 1.66; p=0.060). Among subjects with the highest REVEAL2.0 risk, those with a T allele had worse survival than those no T allele, with best survival among those with low a REVEAL2.0 score and no T allele. Conclusions: In White PAH subjects, rs9493157 associates with human levels of serum CCN2, a known biomarker for PAH. While additional studies are warranted, the T allele associates with worse survival and may enhance the prognostic value of the REVEAL2.0 risk score.

Abstract 4143220: Racial Differences in Prescription of SGLT2 Inhibitors and GLP1 Receptor Agonists Among US Veterans with Type 2 Diabetes and Coronary Artery Disease

Background: Clinical trials have demonstrated that sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) reduce cardiovascular (CV) risk in patients (pts) with type 2 diabetes (T2D) with or at high risk for CV disease. Adoption of new therapies has often lagged for Black pts compared with non-Hispanic White pts, contributing to poorer health outcomes. Methods: We identified Veterans with T2D and angiographic CAD between 2015 and 2020 at 84 Veterans Affairs (VA) medical centers who met eligibility criteria for the EMPA-REG OUTCOME or LEADER trials that first established the clinical efficacy of SGLT2i and GLP1RA, respectively. Within each cohort (SGLT2i- and GLP1RA-eligible), we used multivariable logistic regression adjusted for demographic and clinical covariates to estimate associations of race with evidence-based drug prescription. We evaluated patterns of evidence-based prescription of SGLT2i and GLP1RA over time and by race in US Veterans with T2D and coronary artery disease (CAD). Results: Of 63,561 pts with T2D and CAD, 3,527 Black and 18,668 White pts met trial eligibility criteria for SGLT2i treatment and 2,020 Black and 10,103 White pts for GLP1RA treatment. Evidence-based prescription of both classes increased over time for both races ( Figure ) but reached only approximately 40% for SGLT2i and 15% for GLP1RA in 2023. For SGLT2i, race (Black/White) was not associated with evidence-based prescription (adjusted odds ratio [OR] 0.96, 95% CI 0.89-1.04, P=0.3). However, Black pts were less likely than White pts to receive evidence-based prescription of GLP1RA (adjusted OR 0.85, 95% CI 0.74-0.98, P=0.025). Conclusions: Among pts with T2D and CAD in the VA healthcare system, evidence-based prescription of SGLT2i and GLP1RA increased over time, but many eligible pts remained untreated. Prescription of SGLT2i did not differ by race, but Black pts were less likely than White pts to have evidence-based prescription of a GLP1RA. Disparities in evidence-based use of CV treatments may be specific to certain drug classes, even in a healthcare system with few economic barriers. Further investigation is needed to determine underlying causes and solutions for such disparities.

Abstract 4115832: Statin Intolerance due to Muscle Symptoms Affects Management of Patients: Insights from the CLEAR Outcomes Trial

Background: In CLEAR Outcomes the non-statin bempedoic acid (BA) 180 mg daily reduced MACE-4 (nonfatal MI, nonfatal stroke, coronary revascularization, or CV death) by 13% in 13970 patients at high CV risk with statin intolerance (SI) over a median of 40.6 months. This is the largest prospective database of patients with SI. Aims: To assess whether there were differences in SI symptom history and whether this influenced the clinical course during CLEAR Outcomes. Methods: SI symptoms and impact on activities of daily living (ADL) were recorded prior to randomization. Patients were grouped post hoc as reporting only statin associated muscle symptoms (SAMS), only non-muscle adverse effects (NonSAMS), or BOTH. Results: At baseline 6887 (49.3%) patients reported SAMS, 2485 (18%) NonSAMS, and 4587 (33%) BOTH. SI symptoms had a moderate/severe impact on ADL in 62% SAMS, 48% NonSAMS, and 69% BOTH. Use of any lipid modifying treatment at baseline was 43% SAMS, 36% NonSAMS, and 42% BOTH. Compared to placebo, BA reduced LDL-C at 6 months by 21% in SAMS, 22% in NonSAMS, and 21% in BOTH. There was no difference in the effect on MACE-4 by SI group. New use of moderate/high intensity statin during the study was relatively infrequent (3.2-8.0%) but higher in PBO than BA in all SI groups and was not generally maintained at study end (Table 1). Muscle adverse events (AE) were more frequent and resulted in higher rates of treatment DC in SAMS/BOTH vs NonSAMS (Table 2). There was no difference between BA and PBO in the rate of muscle related AE. Conclusion: SAMS are the predominant cause of SI in patients in CLEAR Outcomes. Patients with a history of SAMS had higher rates of muscle AE and study drug DC due to muscle AE versus NonSAMS. Muscle AE rates and study drug DC were balanced between BA and PBO within each SI symptom subgroup. CLEAR Outcomes exhibits the challenges of treating patients with SI. These data also demonstrate that BA can be useful in reducing CV risk in this patient population.

Abstract 4120229: Shift in body mass index category and associated cardiometabolic risk factors: a post hoc analysis from the SURMOUNT-4 trial

Background: In SURMOUNT-4, participants with obesity demonstrated a mean weight reduction of 21% during the 36-week lead-in with the maximum tolerated dose (MTD) of tirzepatide (TZP). During the 52-week double-blind period, participants who switched to placebo (PBO) experienced a 14% weight regain, while those who continued TZP achieved an additional 6% weight reduction. This post hoc analysis assessed whether participants who shifted to a lower BMI category had improved cardiometabolic factors. Methods: Shift in BMI category (<25 kg/m 2 , 25 to <30 kg/m 2 , 30 to <35 kg/m 2 , 35 to <40 kg/m 2 , and ≥40 kg/m 2 ) from baseline (week 0) during the lead-in period (week 36) and at the primary endpoint (week 88) and from week 36 to week 88 was assessed in participants from SURMOUNT-4 randomized to TZP MTD (N=332) or PBO (N=329). BMI shifts were grouped into “improved” (shift to ≥1 lower category) or “not improved” (stable/attenuated [no change/shift to a higher category]). Changes from baseline in waist circumference, fasting insulin, fasting glucose, HbA1c, vitals and lipid profile were assessed. Results: From weeks 0 to 36, 296 (89%) participants improved in BMI category with TZP, and none had attenuated (Table). From weeks 36 to 88, 130 (39%) participants improved in BMI category with TZP, while the majority (99%) randomized to PBO did not. Overall, from weeks 0 to 88, 304 (92%) vs 189 (57%) participants improved in BMI category with TZP vs PBO, respectively, where the improvements observed in the PBO group originated from the 36-week lead-in period. In general, participants who improved in BMI category at week 88 were noted to have greater improvements in cardiometabolic parameters with TZP vs PBO, including decreases from baseline in waist circumference, fasting insulin, fasting glucose, HbA1c, blood pressure, triglycerides, and cholesterol (total, non-HDL-c, LDL-c, and VLDL-c). Conclusions: In this post hoc analysis of SURMOUNT-4, the majority of TZP-treated participants shifted to lower “improved” BMI categories. Shift to an improved BMI category was accompanied by improved cardiometabolic risk factors, suggesting that TZP treatment may lower further cardiovascular outcomes. Relevant outcomes trials are ongoing.

Abstract 4136724: Early Adoption of Sodium-Glucose Cotransporter-2 Inhibitor Among Patients Hospitalized with Heart Failure and Preserved Ejection Fraction in the United States

Introduction: In August 2021, the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) found that empagliflozin reduced rates of cardiovascular death and hospitalization by 21% in patients with heart failure with mildly reduced ejection fraction of 41-49% (HFmrEF) and with preserved ejection fraction of > 50% (HFpEF). National trends in Sodium-Glucose Cotransporter-2 Inhibitors ( SGLT2i) use among patients with HFmrEF and HFpEF following this trial are unknown. Methods: We identified patients hospitalized for HFmrEF and HFpEF in the AHA Get With The Guidelines-Heart Failure registry between July 2021 and September 2023. We examined temporal trends in SGLT2i prescriptions at discharge after the publication of the EMPEROR-Preserved trial using the Cochran-Armitage trend test. Results: Among 158,849 hospitalizations with an EF > 40% across 557 hospitals, 27,712 (17.4%) had HFmrEF, and 131,137 (82.6%) had HFpEF. Overall, 22,126 (13.9%) patients were discharged with a prescription for SGLT2i, with higher rates among those with HFmrEF (18.5% vs. 13.0% in those with HFpEF). Patients prescribed SGLT2i were more likely to be younger, male, of Black race, have type II diabetes, have Medicaid insurance, and be discharged from large hospitals. After publication of the EMPEROR-Preserved trial during Q3 2021, rates of SGLT2i prescription at hospital discharge increased from 4.2% in Q3 2021 to 23.5% in Q3 2023, with a 29% relative increase in the rate of SGLT2i prescription for each quarter (adjusted OR, 1.29 [95% CI: 1.28, 1.29]; P<.001). Prescription rates increased from 6.1% in Q3 2021 to 31.6% in Q3 2023 among patients with HFmrEF and from 3.8% to 21.9% for patients with HFpEF (Figure). Conclusion: In the U.S., the use of SGLT2i at discharge has increased for patients hospitalized with HFmrEF and HFpEF following the publication of the EMPEROR-Preserved trial. However, the majority of eligible patients hospitalized for decompensated HF remain untreated with SGLT2i, indicating the need for further efforts to apply the scientific findings into clinical practice.

Abstract 4140115: Comparison of Lipoprotein(a) and Other Apo B Containing Lipoproteins as Predictors of Major Adverse Cardiovascular Events in ODYSSEY OUTCOMES

Background: Lipoprotein(a) [Lp(a)] and other atherogenic lipoproteins each contain one molecule of apolipoprotein B (apoB) per particle. Recent studies have suggested that on a per particle basis, Lp(a) is more strongly associated with major adverse cardiovascular events (MACE) than low density lipoprotein. Hypothesis: In statin-treated patients with recent acute coronary syndrome (ACS), we tested the hypothesis that, on a per particle basis, Lp(a) and its change on treatment with alirocumab (ALI) are more strongly associated with MACE than other [non-Lp(a)] apoB-containing particles. Methods: Molar apolipoprotein(a) [corresponding to Lp(a)] and apo B were measured by mass spectrometry at baseline and month 4 (M4) in a subgroup of 11,957 patients who provided consent for use of stored samples in the ODYSSEY OUTCOMES trial. Non-Lp(a) apoB in nmol/L was calculated as total apo B – Lp(a). Lp(a) and non-Lp(a) apo B at baseline in the placebo group, and absolute changes in their levels on ALI, were related to risk of MACE using proportional hazards models. The latter analysis was adjusted for baseline Lp(a) and non-Lp(a) apo B and stratified by baseline Lp(a) (<125 nmol/L and ≥125 nmol/L). Results: Baseline levels of Lp(a) and non-Lp(a) apoB are shown in the Table . In the placebo group, both baseline Lp(a) and non-Lp(a) apo B independently predicted MACE. At M4 in the ALI group, median Lp(a) change from baseline was -40.9 and -7.0 in those with baseline levels ≥ or <125 nmol/L, respectively. Corresponding median changes in non-Lp(a) apoB were -739 and -776 nmol/L (all P<0.001). In the ALI group with baseline Lp(a)>125 nmol/L, the decrease from baseline in Lp(a), but not the decrease in non-Lp(a) apo B, was significantly related to risk of MACE. Among those with baseline Lp(a)≤125 nmol/L, the decrease from baseline in non-Lp(a) apo B, but not in Lp(a), with ALI was significantly related to risk of MACE. Conclusions: On a per particle basis, baseline Lp(a) and non-Lp(a) apo B both predicted MACE. Among those with high baseline Lp(a), reduction in MACE with ALI was predominantly associated with reduction of Lp(a); among those with lower baseline Lp(a) reduction in MACE with ALI was predominantly associated with reduction in non-Lp(a) apo-B. Lp(a) may be an important target of treatment with ALI in those with elevated levels after ACS.

Abstract 4134364: Predicted Low-Density Lipoprotein Cholesterol and Cardiovascular Outcomes Lowering With Inclisiran in Patients With or Without stroke: Insights from SIRIUS in silico trial.

Introduction: Inclisiran, an siRNA, targeting PCSK9 mRNA, reduces LDL-c levels. In SIRIUS in silico trial (NCT05974345), inclisiran was predicted to lower cardiovascular (CV) events in virtual patients with atherosclerotic cardiovascular disease (ASCVD). Research question: This analysis predicted the potential efficacy of inclisiran on CV outcomes in virtual patients with or without prior ischemic stroke (IS). Methods: The SIRIUS trial was conducted using a calibrated and validated knowledge-based mechanistic computational model of ASCVD applied to a virtual population with LDL-C ≥ 70 mg/dL. Each virtual patient was its own control. SIRIUS compared the efficacy of inclisiran vs placebo on top of High Intensity (HI) statin with or without ezetimibe on 3-Point-MACE defined as a composite of time to first occurrence of CV death, nonfatal myocardial infarction (MI) or nonfatal IS over 5 years in patients with or without prior IS. Occurrence of fatal and non-fatal (IS) was also individually assessed in time-to-first-event analyses. Results: Among 204,691 virtual SIRIUS ASCVD patients, 39 371 (19%) had prior IS. At 5 years, the predicted mean percentage reduction in LDL-C with inclisiran as compared to placebo was –49.17% and –49.88% in patients with or without prior IS respectively. Patients with prior IS were at higher risk of 3P-MACE than patients without IS both with placebo and inclisiran (17.01% vs 14.41% with placebo and 13.44% vs 10.83% with inclisiran). However, the predicted rate of 3P-MACE in the inclisiran arm was consistently lower than in the placebo arm for both prior IS and no prior IS (HR 0.78 medium uncertainty and 0.74 low uncertainty respectively). Compared to placebo, inclisiran was also predicted to consistently reduce fatal and non-fatal IS in patients with or without prior IS (5.45% vs 7.22%; HR: 0.75 medium uncertainty and 1.87% vs 2.54%; HR: 0.73 medium uncertainty respectively). Conclusion: SIRIUS provides insights into the potential efficacy of inclisiran on CV events suggesting a substantial 3P-MACE and fatal and non-fatal IS reduction in ASCVD patients including those with prior IS, several years before the availability of results from ongoing outcomes trials (ORION-4, VICTORION-2P).

Abstract 4137516: Disparities in Participation: Analyzing Age, Sex, Race, and Ethnicity in Atrial Fibrillation Clinical Trials in the United States

Introduction: Atrial fibrillation (AF) is a prevalent cardiovascular disease that significantly impacts public health in the United States. Although numerous clinical trials aim to optimize AF management, concerns about demographic disparities in trial participation persist. This study assesses the representation of age, sex, race, and ethnicity among participants in AF trials conducted in the US, highlighting potential biases that could affect the generalizability of trial outcomes. Methods: An extensive review of clinical trials registered on ClinicalTrials.gov involving patients with AF up to April 2024 was performed. The search was filtered to include all completed interventional trials across phases 2 to 4 without restrictions on the initiation or completion dates. Data were extracted concerning mean age, age distribution, sex, and the racial and ethnic composition of the trial participants. Results: From the 173 trials analyzed, a total of 1,355,239 participants were included, with an average age of 64.7 years. The demographic breakdown revealed a participant pool consisting predominantly of older adults (>65 years: 70.8%), with a significant underrepresentation of the younger age group (18-65 years: 29.2%). Males constituted 65.2% of the trial population, highlighting a gender imbalance. Racially, 74.1% of participants were White, while African Americans (7.7%) and Asians (5.9%) and other racial groups were notably underrepresented. Ethnic disparities were also evident, with Hispanic participants making up only 11.5% of the study population. Conclusion: The findings demonstrate significant disparities in the age, sex, race, and ethnic backgrounds of AF clinical trial participants in the US. These imbalances could potentially limit the applicability of trial results across the broader, diverse population. Efforts to enhance the diversity of clinical trial cohorts are essential to ensure more equitable health outcomes and the universal applicability of clinical research findings. Future strategies should focus on targeted recruitment and inclusive study designs to address these disparities.

Transformative Assessment Review

The rapid advancement of generative artificial intelligence (AI) in education and the workforce necessitates that students acquire critical competencies, including digital literacy, data integrity, and ethical AI use, to navigate an increasingly AI-driven world. Equally, academic staff must be upskilled to effectively guide students in the ethical and practical applications of AI. This project examines how a private higher education (HE) institute has modified its Quality Assessment Framework (QAF) to incorporate an AI competence dimension, improve HE assessment and foster students’ competencies. This new dimension complements the existing QAF elements—Intellectual Quality, Significance, and Student Support to ensure a holistic approach in preparing students for AI-integrated academic and professional environments. This project’s framework and innovative tools, such as the enhanced QAF and an AI-driven Generative Pre-trained Transformer (GPT) assessment review tool, support educators in adapting curriculum and assessment design, and empower them to integrate AI competencies seamlessly into the curriculum. The development of these tools drew upon established frameworks, particularly the QAF (Gore et al., 2009) and the AI Assessment Scale (AIAS) by Perkins et al. (2024), which categorises AI usage across five levels, guides assessment reviews and ensures consistent standards for AI integration in student work. A trial, conducted across selected disciplines at the institute, involved academic staff as assessment reviewers and utilised the GPT tool to streamline the assessment review process by aiding in feedback provision, coding, and suggestions for improvement. Evaluation of the tool includes qualitative and quantitative methodologies, gathering academic feedback on usability, clarity, and effectiveness, as well as comparative studies to assess review time and quality before and after GPT integration. Usability testing evaluates workflow compatibility, while academic performance data provide insights into the tool’s impact on student outcomes. Initial results on the tool’s success in enhancing assessment alignment with institutional goals and fostering a comprehensive understanding of AI competence were also examined. Developing and implementing these tools has presented challenges, including the complexity of aligning them with diverse curriculum needs across disciplines, the time investment required for staff training, and the necessity of continuous updates to keep pace with AI technology. Addressing these challenges has been crucial to ensuring the effectiveness and sustainability of these solutions. This digital poster provides insights into the project, covering its development process, trial outcomes, challenges encountered, and future directions for integrating AI competence in higher education assessments.

DDDR-37. OHSV AND RADIATION THERAPIES SENSITIZE GLIOBLASTOMA TO IGF1R-TARGETED THERAPY AND SYNERGIZE IN TRIPLE COMBINATION THERAPY

Abstract Glioblastoma (GBM) continues to have a dismal prognosis despite remarkable advances in the field due to both tumor-intrinsic factors (i.e., IDH1 or EGFRvIII mutations) and extrinsic factors (i.e., relating to the tumor microenvironment (TME)), necessitating therapeutic innovation. Oncolytic herpes simplex virus-1 (oHSV) is an FDA-approved therapy that has shown promising results in clinical trials; however, therapeutic efficacy is limited to a small subset of patients. Thus, elucidating both the tumor-TME interplay and feedback/feedforward tumor-cell signaling in the context of viro-immunotherapy is essential in augmenting therapeutic outcomes. We recently discovered a novel mechanism of resistance to oHSVs, in which infection increases secretion of Insulin-like growth factor 2 (IGF2), activating the Insulin-like Growth Factor-1 Receptor (IGF1R). Upregulation of the IGF1R signaling pathway in GBM is correlated with poor prognosis and has been implicated in resistance to conventional therapies including radiotherapy (RTx). Herein, we further elucidate the impact of oHSVs on IGF1R activation, demonstrating a dose-dependent enhancement of downstream signaling. While IGF1R targeting therapies (e.g., OSI-966, Picropodophyllin (PPP)) have displayed limited efficacy in clinical trials, they significantly increased oHSV-induced cytotoxicity in all tested primary GBM cells compared to either agent alone in vitro and in vivo, resulting in a dose-dependent increase in PARP and caspase 3 activity by western blot and immunohistochemistry. We further found that RTx-induced IGF1 secretion and subsequent IGF1R activation were enhanced when combined with oHSV treatment. Triple combination therapy with oHSV, IGF1R inhibition, and RTx significantly increased tumor cell killing in vitro and improved survival of orthotopic GBM tumor-bearing mice. Collectively, our study provides preclinical evidence of enhanced therapeutic efficacy of oHSVs and RTx in combination with IGF1R blockade, supporting future use of IGF1R inhibitors in combination with the standard of care and FDA-approved oHSV therapies in patients with GBM.

TMOD-33. DOES PRE-CLINICAL DRUG ACTIVITY PREDICT PHASE II CLINICAL EFFICACY IN GLIOBLASTOMA? A DETAILED ANALYSIS

Abstract Despite decades of research, there are fewer than six FDA-approved therapies for glioblastoma (GBM). The drug approval process relies on studies establishing pre-clinical activity, most commonly using murine models, followed by in human studies establishing safety and then efficacy. Although murine models for GBM have allowed for insights into tumor biology, their utility in assessing the efficacy of novel anti-cancer therapies remains highly debated. Here, we sought to establish whether there was any relationship between drug activity in preclinical models and phase 2 clinical trial outcomes. Using ClinicalTrials.gov (NIH), all phase 2 trials in glioblastoma up to December 2023 were queried and downloaded. Trials that were never started, had not yet started, were withdrawn, not completed, or contained indications beyond glioblastoma were excluded. Studies examining anti-tumor effects of an investigational agent with or without bevacizumab, temozolomide, or radiation therapy in glioblastoma were included, and studies examining alternative dosing strategies, various medical devices, or drug combinations, were excluded. The corresponding preclinical studies were identified via literature review for each clinical trial. Data including the progression free and overall survival benefit, mouse models used, and sample sizes were extracted from each study. 659 trials between 1994 and 2023 were included for analysis. Of these, 272 (41%) were for monotherapies, examining 90 unique small molecules. Preclinical endpoints included murine survival and tumor weight. In comparing mouse survival and tumor size to progression free and overall survival in humans, our preliminary analysis did not reveal any clear correlation. The correlation between preclinical and clinical drug response in GBM remains uncertain. Future work will examine whether mouse genotype, immune status, or GBM cell line used affected the degree of concordance with human clinical trial data. Our analysis suggests that further investigation into preclinical models of GBM, and standardized reporting of preclinical models, are needed.

PATH-12. CLINICAL AND NEUROPATHOLOGICAL MARKERS FOR DISTINGUISHING BETWEEN IDH-MUTANT ASTROCYTOMAS OF WHO GRADE 2 AND 3

Abstract BACKGROUND The neuropathological criteria of anaplasia to distinguish between IDH-mutant astrocytomas of WHO grade 2 and 3 are ill-defined by the WHO 2021 classification. Following the positive phase III trial results and the expected approval of Vorasidenib for grade 2 astrocytomas, identifying prognostic markers distinguishing grade 2 and 3 tumors remains crucial. METHODS We retrospectively searched our institutional database for patients meeting the diagnostic criteria for IDH-mutant astrocytomas per the WHO 2021 classification. Clinical, neuropathological, and molecular data were collected, and outcomes compared using log-rank analysis. Centralized slide review is ongoing to exclude inter-rater variability due to the study’s retrospective nature. RESULTS We identified 99 patients with IDH-mutant astrocytomas in which detailed neuropathological and clinical information were available for review, including 63 tumors (63.6%) which were assigned to WHO grade 2 and 36 tumors (36.4%) assigned to WHO grade 3. At a median follow-up of 7.5 years, median progression-free survival was 5.7 years for WHO grade 2 tumors and 4.4 years for WHO grade 3 tumors. Median overall survival for WHO grade 2 and WHO grade 3 tumors was not reached. On univariate analysis, higher WHO grade, an increased number of mitoses, elevated Ki67 indices and the presence of contrast-enhancement on pre-operative imaging were associated with less favourable outcome. However, only the presence of contrast-enhancement retained its prognostic significance when forwarded into a multivariate model (p = 0.034 for overall survival, p = 0.012 for progression-free survival). The findings on the association between contrast-enhancement and outcome were confirmed in treatment-based subgroups, including individuals treated with a watch-and-scan approach (n = 30), radiotherapy (n = 25), or chemotherapy (n = 33). CONCLUSION While our findings await confirmation in larger prospective cohorts, neuropathological criteria for anaplasia might need to be accompanied by clinical information including contrast enhancement to prognostically distinguish grade 2 from grade 3 tumors particularly in patients undergoing biopsy given the risk for undersampling.

Pengembangan Media Pembelajaran Go Puzzle Pada Mata Pelajaran Pendidikan Pancasila dan Kewarganegaraan untuk Siswa Sekolah Menengah Pertama

This study aims to develop and test the validity, attractiveness, effectiveness, and applicability of Go Puzzle learning media in the subjects of Pancasila and Civic Education. The procedure used is research and development based on the steps proposed by Borg and Gall. The products produced in this development study are Go Puzzle learning media material for the Formulation and Determination of Pancasila as a State Basis that is valid, interesting, effective, and can be applied in learning. The product validity test is based on the results of material expert validation of 92.78 percent, media expert validation of 91.42 percent, expert validation of learning implementation plans of 95.63 percent, and field learning expert validation of 98.21 percent. The product attractiveness test is based on the results of small group trials of 90.36 percent and the results of large group trials of 93.46 percent. The product effectiveness test is based on the results of large group trials which resulted in an average completeness of students’ scores when pretest was 20.89 percent and post test was 86.89. This shows that there is an increase in the percentage of completeness of scores obtained by students, which is 66 percent. The product applicability test is based on the educator response questionnaire, which is 96.88% which shows that the product developed can be applied in learning. Abstrak: Kajian ini bertujuan untuk mengembangk