Citations

Abstract Background Primary aldosteronism (PA) is a common treatable cause of hypertension. When caused by unilateral adrenal disease, it is potentially curable by adrenalectomy. However, specialized tests and other factors may delay definitive treatment. We assessed the time to adrenalectomy (TTA) for patients worldwide. Methods We conducted an international, multicentre retrospective study involving 39 centres from 15 countries to determine the total time taken from the first presentation to adrenalectomy and the intervals between each stage (screening, confirmatory, subtyping, and adrenalectomy). We included patients with PA who underwent adrenalectomy from January 1, 2018, to October 30, 2022. Post-adrenalectomy outcomes were evaluated using the Primary Aldosteronism Surgery Outcome criteria. We performed multivariable quantile and linear regression to identify characteristics associated with longer TTA. Results We included 861 patients, mean age 49.3 ± 11.1 years, and 44.5% were women. Overall median TTA was 13.5 months, IQR: 6.6-24.5. Median intervals were 0.1 months (screening), 1.0 months (confirmatory), 4.1 months (subtyping), and 4.3 months (adrenalectomy). On multivariable analysis, median TTA was increased by 5.4 months for each additional adrenal vein sampling (AVS) procedure. Other factors associated with longer TTA included adrenalectomy post-COVID-19, younger age, and additional screening tests. Compared with countries with routine AVS, those without AVS had a shorter TTA (6.1 vs 15.1 months, P < .001), but greater likelihood of absent/partial biochemical success post-adrenalectomy (27.4% vs 12.4%, P < .001). Conclusion Primary aldosteronism management is time-consuming worldwide, especially for subtyping tests and adrenalectomy. While omitting AVS reduces overall time, patients are less likely to achieve biochemical cure post-adrenalectomy.

ABSTRACT Background Sodium‐glucose cotransporter 2 inhibitors (SGLT2‐Is) are primarily used to manage type 2 diabetes mellitus (T2DM) and heart failure (HF), but their impact on reducing stroke risk in patients with atrial fibrillation (AF) remains underexplored. We aimed to investigate the impact of SGLT2‐Is for stroke risk mitigation in patients with AF. Methods Using the TriNetX database, we performed a retrospective cohort study on patients ≥ 18 years with AF and on anticoagulation. These patients were then classified into two cohorts based on their use of SGLT2‐Is. To balance the baseline demographics, comorbidities, and medication use, propensity score matching (PSM) was used. The primary outcome was ischemic and hemorrhagic strokes, and the secondary outcomes were all‐cause mortality, all‐cause hospitalizations, need for AF cardioversion or antiarrhythmic drug initiation, and cardiac arrest. Adjusted odds ratio (aORs) and hazard ratios (HRs) were estimated for both the primary and secondary outcomes. Results A total of 152,778 patients with 76,389 patients were included in each cohort (SGLT2‐Is users, and non‐users) after PSM. The mean age of both SGLT2‐Is users and non‐users was 72.8 years. For the SGLT2‐Is users, the mean follow‐up period was 317 days, whereas the mean follow‐up period for the non‐users was 306 days. For the primary outcome, we found that SGLT2‐Is users had a lower risk of ischemic stroke (aOR: 0.889; 95% CI: 0.857–0.923) and hemorrhagic stroke (aOR: 0.682; 95% CI: 0.620–0.749) compared to non‐users. Regarding the secondary outcomes, SGLT2‐Is users also had lower risk for all‐cause mortality (aOR: 0.615; 95% CI: 0.595–0.636), all‐cause hospitalizations (aOR: 0.599; 95% CI: 0.587–0.611), need of AF cardioversion (aOR: 0.846; 95% CI: 0.813–0.881), antiarrhythmic drug initiation (aOR: 0.790; 95% CI: 0.766–0.815), and cardiac arrest (aOR: 0.643; 95% CI: 0.601–0.688). Conclusions SGLT2‐I use in patients with AF is associated with lower risks of stroke and other cardiovascular and non‐cardiovascular outcomes. Future prospective research is needed to validate these findings.

3040 Background: EVEREST-2 is a first-in-human, phase 1/2 trial to assess the safety and efficacy of A2B694, an autologous, logic-gated Tmod CAR T therapy targeted to MSLN, which is normally expressed in the mesothelium and can be upregulated in many solid tumors. A2B694 is designed to overcome challenges of on-target, off-tumor toxicity that have limited other MSLN-targeted approaches by combining a CAR-activating receptor targeting MSLN with a blocker CAR that recognizes HLA-A*02, to distinguish between normal and tumor cells (Tokatlian, et al. J Immunother Cancer. 2022). Methods: Adults with recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression who have progressed after standard-of-care therapy are eligible for EVEREST-2. Enrollment to EVEREST-2 and collection of T-cells occurs through the ongoing prescreening study BASECAMP-1 (NCT04981119). When clinically appropriate, A2B694 is manufactured from cryopreserved T cells, and patients undergo lymphodepletion before A2B694 infusion. The dose-escalation phase is evaluating the safety and tolerability of A2B694 to identify the recommended phase 2 dose (RP2D). Dose escalation was started at 1x10 8 Tmod positive cells (dose level [DL] 1) and will increase up to 14x10 8 in combination with low-dose IL-2 (DL 5). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B694. Results: As of January 15, 2025, 5 participants (median age: 60 years; range, 50-84) have enrolled on EVEREST-2 and received A2B694 at DLs 1-2; participants had ovarian cancer (n = 3), pancreatic cancer (n = 1), and non-small cell lung cancer (n = 1) and had received a median of 4 prior lines of therapy (range, 1-7). Lymphodepleting chemotherapy was well tolerated with no significant cytopenias observed. The most common adverse events were lymphopenia (7 [14.6%]) and decreased appetite (6 [12.5%]). There were no dose-limiting toxicities, cytokine release syndrome, nor related neurotoxicity. One participant was admitted to the hospital for decreased appetite. No long-term toxicities have been noted up to 7.5 months post-infusion. Of the participants who have received A2B694, 5 were efficacy evaluable at DLs 1-2. A2B694 was detected post-infusion in the peripheral blood in all patients. Additionally, A2B694 was detected in an abdominal tumor biopsy from a patient with pancreatic cancer 42 days post-infusion. Conclusions: The logic-gated approach was successful at reducing toxicity seen with prior MSLN-targeted CAR T therapies, and A2B694 showed successful CAR T expansion and tumor infiltration. The maximum tolerated dose has not been reached, and results from the dose-escalation phase continue to determine the RP2D. Clinical trial information: NCT06051695 .

Importance Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective To estimate the worldwide burden of SAH. Design, Setting, and Participants Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures SAH and 14 modifiable risk factors. Main Outcomes and Measures Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor–specific population attributable fractions (PAFs). Results In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and Relevance Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.

Objective: To establish benchmark cutoffs for robotic liver resection (R-LR), encompassing both major and minor resections, and to determine the impact of patient selection on outcomes. Background: R-LR is a key advancement in minimally invasive liver surgery but lacks standardized benchmarks, especially for minor resections. While guidelines endorse R-LR, its role in optimizing outcomes remains unclear. This study establishes the first benchmarks for R-LR, enabling comparisons across surgical modalities and refining patient selection. Methods: This retrospective, multicenter study analyzed consecutive adult patients undergoing R-LR at 30 international centers (2020–2023). Benchmark centers had an annual case volume of ≥15 R-LR. Benchmark criteria included ASA ≤2, no major comorbidities, no prior liver resections, and Child-Pugh A status. Benchmark cutoffs for 14 key outcomes were set at the 50th and 75th percentiles of median values across benchmark centers. Multivariable logistic regression identified predictors of textbook outcomes. Results: Eighteen high-volume centers contributed 4028 cases with 2632 (65.3%) meeting benchmark criteria. Malignancy was the indication in 29.6%, most commonly hepatocellular carcinoma followed by colorectal liver metastases. Major liver resection was performed in 42.6%. The distribution of Iwate difficulty scores was low (25.4%), intermediate (53.9%), advanced (15.9%), and expert (4.9%). Benchmark cutoffs were established for minor and major resection, and stratified by Iwate low (0-3), intermediate (4-6) and high (7-12): Open conversion (≤6.5% minor, ≤10.5% major), major complications within 90 days (≤5.2% minor, ≤16.7% major), R1 resection (≤9.2% minor, ≤6.7% major). Benchmark cases performed at low-volume centers were able to achieve outcomes within the corresponding benchmark cutoffs. In fact, patient selection reflected by the proportion of benchmark patients, rather than case volume, was associated with textbook outcomes. Conclusions: This study defines R-LR benchmarks, emphasizing patient selection over center volume for optimal outcomes. Benchmark cutoffs guide training and support the expansion of R-LR.

Abstract Background/Introduction Access to timely healthcare in disadvantaged areas remains essential to achieving equitable health outcomes, especially in regions facing structural and social vulnerabilities. Purpose To assess wait times for cardiovascular disease consultations in US-Mexico border regions compared to non-border regions among US Veterans. Methods This cross-sectional analysis included all veteran cardiovascular consultations referred through the Veterans Choice Program to community healthcare centers from 2014 to 2020. We obtained the average wait times in days for consultation approval, scheduling, completion, and total wait time from approval to consultation completion. All consultations were classified by county of residence as either within a US-Mexico border region or a non-border region, as per the La Paz Agreement. Multivariable linear regression analyses were performed to evaluate the impact of border status on average wait times. ARIMA modeling was completed to estimate forecasted wait times during the COVID-19 pandemic. Results A total of 485,158 consultations related to outpatient cardiovascular disease were retrieved from the VA Healthcare System. Amongst these, 461,696 of the consultations were placed in non-border regions whereas 23,462 consultations were placed in US-Mexico border regions. The most common consultation requests were made for general cardiology clinic (n=365,227), echocardiography (n=32,017), cardio-pulmonary rehabilitation (n=40,699), and cardiac stress testing (n=16,258). Wait times for cardiovascular disease consultations were not higher in US-Mexico border counties than in non-border regions. For electrophysiology consultations specifically, border counties exhibited significantly shorter total wait times (coeff = -10.81, p=0.008). Additionally, while the COVID-19 pandemic led to increased total wait times in non-border areas (Figure 1), total wait times in border regions remained stable during this period (Figure 2). Conclusions Our findings suggest that US-Mexico border region status does not result in longer wait times for cardiovascular disease consultations, with the exception of shorter wait times for electrophysiology services. This study provides important insights into the unique dynamics of healthcare access in structurally disadvantaged regions, highlighting that wait times are not a significant barrier to cardiovascular care in border areas, and emphasizes the need to consider regional differences in healthcare delivery policies.

Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) have emerged as a vital component in the management of heart failure (HF), demonstrating significant improvements in cardiac function. However, their impact on outcomes in patients with acute myocardial infarction (AMI) remains poorly characterized. This study aimed to evaluate the long-term outcomes of SGLT2-Is among patients with AMI. Methods We conducted a retrospective cohort study using data from the TriNetX Banner Health Network platform in the United States, including patients aged ≥18 years with AMI identified through ICD-10 codes. Patients were categorized into two cohorts based on SGLT2-I use. Propensity score matching (PSM) was performed to balance baseline demographics, comorbidities (e.g., hypertension, diabetes, chronic kidney disease, heart failure, and hyperlipidemia), and medication use (e.g., heart failure therapies, antiplatelet agents, anticoagulants). Risk ratios (RRs) and 95% confidence intervals (95% CIs) were estimated for the following cardiovascular outcomes: acute HF hospitalizations, stroke, all-cause hospitalizations, recurrent AMI, cardiac arrest, and new-onset atrial fibrillation (AF). Kaplan-Meier analysis was completed to estimate survival probability from all-cause hospitalizations. Results After PSM, 2,440 patients were analyzed (1,220 SGLT2-I users; 1,220 non-users). Both cohorts had similar characteristics without any residual imbalance: mean age 67.7 years in the SGLT2-I group vs. 67.5 years in non-users, and both groups included 85.2% White and 33.6% female patients. Mean follow-up duration was 608 days for SGLT2-I users and 1,013.5 days for non-users. SGLT2-I use was associated with significantly lower rates of all-cause hospitalizations (RR: 0.712; 95% CI: 0.652–0.777), HF-related hospitalizations (RR: 0.878; 95% CI: 0.781–0.987), recurrent AMI (RR: 0.821; 95% CI: 0.703–0.959), and cardiac arrest (RR: 0.500; 95% CI: 0.345–0.725). No significant differences were observed in stroke (RR: 0.909; 95% CI: 0.702–1.178) or new-onset AF (RR: 0.889; 95% CI: 0.782–1.010) between the cohorts. Conclusions SGLT2-Is are associated with improved cardiovascular outcomes in patients with AMI, including reductions in all-cause and HF-related hospitalizations, recurrent AMI, and cardiac arrest. While these findings are hypothesis-generating, they emphasize the need for prospective clinical trials to confirm these results.Kaplan-Meier Analysis.

Abstract Aims Sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) improve heart failure (HF) outcomes but their effects on acute myocardial infarction (AMI) remain poorly characterized. This study aimed to evaluate the 1-year cardiovascular outcomes of SGLT2-Is among patients with AMI. Methods and results We conducted an observational, retrospective cohort study using TriNetX data, including patients aged ≥18 with AMI identified via ICD-10 codes regardless of left ventricular ejection fraction (LVEF), categorized by SGLT2-Is use. Propensity score matching (PSM) was performed to balance baseline demographics, comorbidities, and medication use. Adjusted odds ratios (aORs) were estimated for the primary outcome (recurrent AMI) and the secondary outcomes (acute HF hospitalizations, stroke, all-cause hospitalizations, all-cause mortality, new-onset atrial fibrillation, and cardiac arrest). After PSM, 89 554 patients were analysed (44 777 SGLT2-Is users; 44 777 non-users). The mean age was ∼68 years in both cohorts with a similarly high burden of cardiovascular comorbidities. Mean follow-up duration was 290.854 days for SGLT2-Is users and 284.465 days for non-users. SGLT2-Is use was linked to lower rates of recurrent AMI [aOR: 0.459; 95% confidence interval (CI): 0.367–0.551], all-cause hospitalizations (aOR: 0.782; 95% CI: 0.762–0.803), all-cause mortality (aOR: 0.640; 95% CI: 0.612–0.670), and cardiac arrest (aOR: 0.834; 95% CI: 0.773–0.900). No differences were observed in acute HF hospitalizations, new-onset atrial fibrillation, or stroke. Conclusion SGLT2-Is are associated with improved cardiovascular outcomes in patients with AMI, including reductions in recurrent AMI, all-cause hospitalizations and mortality, and cardiac arrest. These findings emphasize the need for prospective clinical trials involving patients with AMI and other cardiovascular comorbidities, regardless of LVEF, to confirm these results.

Abstract Background: Fibroblast activation protein (FAP) is a type II integral membrane glycoprotein, highly expressed on the cell surface of cancer-associated fibroblasts (CAFs) present in the tumor microenvironment of most epithelial cancers and showing limited expression in normal tissues. Given this expression profile, FAP appears to be a promising target for radioligand therapy that has pan-cancer potential. [177Lu]Lu-NNS309 is a FAP-targeted radiopharmaceutical that shows improved tumor retention and demonstrates promising anti-tumor activity in translationally relevant preclinical models (e.g., PDAC, NSCLC) where FAP is expressed on CAFs. Methods: CFXX489A12101 (NCT06562192) is a first-in-human phase I, open-label, multi-center study of [177Lu]Lu-NNS309 in patients with pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), breast cancer (BC), and colorectal cancer (CRC). The study includes a dose escalation part followed by a dose expansion part. Key eligibility criteria include prior treatment for locally advanced unresectable or metastatic disease and having all measurable lesions (per RECIST 1.1) showing [68Ga]Ga-NNS309 uptake on positron emission tomography/computed tomography (PET/CT). Patients who are eligible for treatment receive one dose of [177Lu]Lu-NNS309 on day 1 of each cycle. A 6-week and a 4-week dosing schedule will be explored. Dosimetry data will be obtained from patients in the dose escalation part after the first dose and will be used to calculate the cumulative radiation exposure. Dose escalation will be guided by a Bayesian hierarchical logistic regression model with overdose control (EWOC) principle, and assessment of all relevant data available from all dose levels including safety, tolerability, clinical dosimetry, pharmacodynamics, and preliminary efficacy. Once the recommended dose(s) (RD) and schedule(s) of [177Lu]Lu-NNS309 are determined, the expansion part may open and will include patients with locally advanced or metastatic PDAC (n∼20), locally advanced or metastatic NSCLC (n∼20), HR+/HER2- ductal BC (n∼15), HR+/HER2- lobular BC (n∼15), and triple negative BC (; n∼24).The primary objectives of the study are to evaluate the safety and tolerability of [177Lu]Lu-NNS309 and to identify the RD(s) and regimen(s) of [177Lu]Lu-NNS309 for further clinical evaluation. Secondary objectives of the study are to evaluate the preliminary anti-tumor activity of [177Lu]Lu-NNS309, characterize the pharmacokinetics of [177Lu]Lu-NNS309 in blood and urine, the radiation dosimetry for organs and tumor lesions, and to evaluate the safety and imaging properties of [68Ga]Ga-NNS309. Conclusion: The study is currently enrolling in the dose escalation part. Citation Format: Ravit Geva, Daniel Juneau, Shadi Abdar Esfahani, Cristiano Ferrario, Farshad Moradi, Amir Iravani, Jordi Ahnert, Ivan Manuel Victoria Ruiz, Thibaud Koessler, Aitana Calvo Ferrandiz, Bernard Doger de Speville, Patrick Flamen, Albiruni Razak, Desiree Deandreis, Laure Al-Mansour, Niklaus Schaefer, James Nagarajah, Hilde Nienhuis, Marco Maccauro, Angelina Filice, Jonathan Goldman, Ken Herrmann, Matthias Eiber, Alexander Drzezga, Martin Heuschkel, Jonathan McConathy, Johnson Geoffrey, Ephraim Parent, Yasutoshi Kuboki, Shizuka Origuchi, Xuan Mai Couillebault, Elisa Garcia Garayoa, Jayarama Naidu Roopa, Christopher Straub, Dominik Hainzl, Xinyu Chen, Fang Yang, Eirini Pectasides, Brandon Mancini. Phase I open-label, multi-center study to evaluate the safety, tolerability, dosimetry, and preliminary activity of FXX489 ([177Lu]Lu-NNS309) in patients with pancreatic, lung, breast and colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT112.