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In the phase III placebo-controlled DeFi trial (ClinicalTrials.gov identifier: NCT03785964 ) primary analysis, nirogacestat showed significant improvement versus placebo in progression-free survival (PFS), objective response rate (ORR), and patient-reported outcomes (PRO) in adult patients with progressing desmoid tumors (DT; median [range] exposure: 20.6 [0.3-33.6] months). Here, long-term nirogacestat efficacy and safety were evaluated in patients randomly assigned to nirogacestat and followed through the final data cutoff date of December 19, 2024. End points included PFS and ORR per RECIST v1.1, PRO, and safety. The median (range) duration of exposure was 33.6 (0.3-61.8) months. Median PFS was not reached. The ORR with up to 4 years of nirogacestat treatment was 45.7% (32 of 70), with three additional partial and three additional complete responses since the primary analysis. Further target tumor size reduction occurred in most patients. Benefits in PROs were sustained while on treatment. Frequently reported treatment-emergent adverse events (TEAEs) decreased in incidence and severity over time. Since the primary analysis, four patients discontinued nirogacestat because of TEAEs between years 2 and 4. In conclusion, long-term continuous nirogacestat treatment was associated with further tumor size reductions, durable objective responses, sustained PRO benefits, and a manageable safety profile consistent with the primary analysis.

Background: Hypertension is a major risk factor for cardiovascular disease, yet nearly 46% of adults with hypertension remain undiagnosed. Without timely intervention, it can lead to severe complications, including stroke, heart failure, and kidney disease. In sub-Saharan Africa (SSA), hypertension prevalence varies widely from 19.3% in Eritrea to 39.6% in Seychelles. Urbanization has played a key role in increasing hypertension rates through its impact on diet, physical activity, and obesity. Still, urban-rural differences remain modest. Understanding demographic and lifestyle predictors is crucial for SSA's targeted prevention and control efforts. Methods: We conducted a cross-sectional analysis using nationally representative, de-identified data from the Demographic and Health Surveys (2016–2024) in five SSA countries: Lesotho, Tanzania, Gabon, Benin, and South Africa. Adults aged ≥18 years with valid blood pressure and covariate data were included (N=38,085). Blood pressure was measured three times, and the average of the second and third readings was used when available. Hypertension was defined per the 2017 ACC/AHA guidelines (SBP ≥130 mmHg or DBP ≥80 mmHg). Independent variables included age, sex, BMI, education, wealth index, smoking status, and recent caffeine intake. Results: Urban residents (n=20,773) had a higher hypertension prevalence than rural residents (n=17,312) (44.8% vs. 36.7%, p<0.001), along with higher median BMI (24.9 vs. 22.3 kg/m 2 ) and obesity rates (23.5% vs. 11.3%). South Africa exhibited the highest rates (urban 68%, rural 61%), while Tanzania and Lesotho had the lowest (~39–40%). In pooled multivariable analysis, hypertension odds increased steadily with age (OR 4.57 for ≥60 vs 18–24, p<0.001). Obesity demonstrated a dose–response relationship: Class III obesity was associated with a fivefold increase in risk (OR 5.38, p<0.001). Men had higher odds than women (OR 1.65, p<0.001). Secondary education and middle wealth status conferred modest increases in risk. Caffeine use was marginally significant; smoking was not. Predictor importance ranked: age > BMI > sex > wealth > education > smoking > caffeine. Conclusion: Hypertension is highly prevalent in both urban and rural SSA, with age and obesity emerging as the most powerful predictors. South Africa stands out with younger adults most affected. Early detection, awareness campaigns, and obesity-focused interventions are needed to mitigate the growing burden of hypertension in SSA.

Abstract Aims To assess the performance of an artificial intelligence-enabled electrocardiogram (AI-ECG) algorithm in identifying patients with moderate to severe aortic stenosis (AS) in an Asian cohort from a tertiary care centre. Methods and results We identified a randomly selected patients ≥60 years old who underwent echocardiography and ECG within in 31 days between 2012 and 2021 at the Samsung Medical Center in Korea. Patients with previous cardiac surgery, prosthetic valves, or pacemakers were excluded. The AI-ECG model, originally developed and validated by Mayo Clinic in the USA, was applied without fine-tuning. Performance metrics, including the area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy, were calculated to compare AI-ECG predictions with TTE-confirmed AS status. Among 5425 patients, 1095 had moderate to severe AS, and 4330 age- and sex-matched patients without AS were included as controls. The AI-ECG model achieved an AUC of 0.85 (95% CI: 0.84–0.87) in detecting moderate to severe AS. Sensitivity, specificity, PPV, NPV, and accuracy were 0.83, 0.65, 0.37, 0.94, and 68.29%, respectively. The model's performance was consistent across various age and sex subgroups, with sensitivity increasing in older patients. Conclusion The AI-ECG model developed in the USA demonstrated comparable performance in detecting moderate to severe AS in an Asian cohort compared with its original validation population. These findings highlight the potential utility of AI-ECG as a non-invasive screening tool for AS across diverse patient populations.

OBJECTIVE The aim of this study was to evaluate mortality and progression outcomes in patients undergoing stereotactic radiosurgery (SRS) for breast cancer brain metastases and to identify associated risk factors using a national quality registry. METHODS The NeuroPoint Alliance (NPA) SRS Registry was employed for this study, which conducted prospective enrollment of patients undergoing SRS at 16 participating centers from 2017 to 2024. Outcomes of interest included the post-SRS EQ-5D score change, overall survival, local progression, out-of-field progression, and overall intracranial progression. For all time-to-event analyses, Kaplan-Meier curves and multivariable Cox regressions with hazard ratios were used. RESULTS A total of 138 patients (127 female, mean age 59.8 years) were identified; 46.4% had a single lesion, 42.0% had 2–4 lesions, and 11.6% had ≥ 5 lesions, while 87.0% had a Karnofsky Performance Status (KPS) score between 80 and 100. The median overall survival was 17.9 months, and independent predictors of all-cause mortality included a KPS score ≤ 90 (HR 6.73) and diabetes mellitus (HR 3.35). The median time to local progression was 19.8 months. More than 5 lesions at baseline (HR 9.03) and a marginal dose ≤ 17.6 Gy (HR 8.00) were predictive of local recurrence. The median was not reached for out-of-field progression, and predictors included ≥ 2 lesions at the time of SRS (HR 3.20) and a marginal dose ≤ 17.6 Gy (HR 4.61). At the final follow-up assessment, 17.1% of patients experienced no change according to the EQ-5D, while 34.3% had improvement, 11.4% had mixed results, and 37.1% had worsened health. In the multivariable linear regression model, pre-SRS resection (r = 1.92) and baseline EQ-5D score (r = 1.29) were statistically significant predictors of quality of life at the final follow-up assessment. CONCLUSIONS Using real-world data from the NPA SRS Registry, this study demonstrated comparable outcomes in patients who underwent SRS for breast cancer brain metastases compared with those of previous literature. The number of lesions at the time of SRS and the marginal dose were independent risk factors for local recurrence, out-of-field progression, and overall intracranial progression. Pre-SRS resection and baseline EQ-5D score were independent predictors of quality of life following SRS.

Objective To assess the association between educational level and cardiovascular age acceleration metric derived from ECG, and to determine whether this association is mediated by established cardiovascular disease (CVD) risk factors. Design Prospective population-based cohort study (the Tromsø Study). Setting General population of the Tromsø municipality, Norway. Participants The study sample consisted of 4367 participants of the Tromsø Study, who took part in both Tromsø6 (2007–2008) and Tromsø7 (2015–2016), had a 12-lead ECG obtained at Tromsø7 and did not report a history of heart attack, stroke or atrial fibrillation. Primary outcome measures δ-age, a biomarker of cardiovascular ageing, is defined as the difference (in years) between an individual’s ECG-predicted heart age and their chronological age. ECG-predicted heart age was estimated using a previously validated deep neural network. Results Our findings indicate an inverse association between education and δ-age, with a regression coefficient per increment increase in education of −0.24 (95% CI −0.41 to –0.07) in the overall sample, −0.38 (95% CI −0.59 to –0.16) for women and −0.04 (95% CI −0.31 to 0.23) for men. Participants with the highest level of education (university/college for 4 or more years) had the lowest estimated δ-age with a regression coefficient of −0.69 years (95% CI −1.23 to –0.16) compared with the group with primary education for the overall sample, −1.05 years (95% CI −1.73 to –0.37) for women and −0.15 years (95% CI −1.03 to 0.73) for men. CVD risk factors mediated up to 75% of the association between overall education and δ-age, and 80% of the association among those with the highest education level (university/college for 4 or more years). Among women, 50% of the effect of overall education on δ-age was mediated by CVD risk factors, rising to 53% in the category with the highest level of education. However, in the subsample of men, there was no significant association between education and δ-age, and the mediation analysis produced natural direct and indirect effects pointing in opposite directions. Conclusions Cardiovascular ageing is inversely associated with educational level, an effect that appears to be largely mediated through established risk factors.

Recent advancements in computed tomography have significantly transformed the clinical application of this technique in diagnosing and managing coronary artery disease (CAD). Computed tomography coronary angiography (CTCA) has emerged as a leading non-invasive imaging modality, often serving as the first-line investigation to exclude obstructive CAD in patients with chronic coronary syndrome. Beyond its utility in diagnosing CAD, CTCA has become instrumental in procedural planning for percutaneous coronary intervention (PCI), particularly in complex cases such as left main stem (LMS) interventions, where peri-procedural risks are elevated. This review highlights the evolving role of CTCA in LMS PCI, underscoring its clinical utility in improving procedural precision and, subsequently, patient outcomes. Recent technological advancements, including detailed multiplanar and three-dimensional (3D) reconstructions, CT-derived fractional flow reserve (CTFFR), and the integration of artificial intelligence (AI) algorithms, have expanded the capabilities of CTCA. These innovations allow for comprehensive anatomical and functional assessments, enabling precise plaque morphology, lesion complexity, and bifurcation anatomy evaluations alongside PCI simulations. By offering detailed insights into coronary vasculature and lesion characteristics, CTCA provides critical information for optimising LMS PCI strategies. This review explores the current applications and future potential of CTCA in guiding LMS PCI, highlighting its role in improving procedural planning, risk assessment, and overall management of this challenging patient population.

TPS11580 Background: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract. KIT and platelet-derived growth factor receptor α ( PDGFRA ) mutations remain the key oncogenic drivers in the majority of patients with advanced GIST, with acquired secondary drug-resistant mutations contributing to the heterogeneity and complexity of the disease. The diversity of these resistance mutations allows escape from standard-of-care tyrosine kinase inhibitor (TKI) therapy, creating an unmet need for novel therapies that inhibit all clinically relevant GIST-driving mutations. DCC-3009 is an investigational, highly potent, and selective switch-control KIT and PDGFRA inhibitor designed to act against known clinically relevant primary and secondary GIST-driving mutations while limiting off-target effects. Preclinical data showed that DCC-3009 has strong antitumor effects in xenograft models driven by resistant KIT mutations, optimized solubility and oral bioavailability, and low risk of cytochrome P450 inhibition. Here, we describe an ongoing phase 1/2 study evaluating DCC-3009 as a monotherapy in patients with advanced GIST. Methods: This study is a multicohort, open-label, phase 1/2 trial evaluating the safety, tolerability, and efficacy of DCC-3009 in patients with advanced GIST (NCT06630234). This trial uses a modular approach, with each module defined according to the therapy (DCC-3009 alone or in combination with other anticancer agents) and divided into 2 parts (dose escalation and dose expansion). For inclusion in the DCC-3009 monotherapy dose escalation, adult patients (≥18 years) must have histologically or cytologically confirmed advanced GIST with documented KIT or PDGFRA mutation and progression on or intolerance to at least 1 approved TKI regimen in the advanced setting (imatinib if KIT -mutant). Patients must have at least 1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST v1.1) and an Eastern Cooperative Oncology Group Performance Status of 0 or 1 at screening. Exclusion criteria include receiving systemic anticancer therapy (encompassing investigational agents) within 14 days or less than 5 half-lives, radiotherapy within 14 days prior to first dose of study drug, prior or concurrent malignancy requiring treatment or expected to need treatment for active cancer, known allergy or hypersensitivity to the study drug components or any of its excipients, and impaired oral absorption or malabsorption syndrome. Enrolled patients across monotherapy dose escalation will receive DCC-3009 orally in 28-day cycles. The primary outcome measures for monotherapy dose escalation include safety assessment. Secondary outcome measures include objective response rate, duration of response, and progression-free survival by mRECIST v1.1, as well as overall survival and pharmacokinetics. Clinical trial information: NCT06630234 .

11506 Background: Catequentinib Hydrochloride (AL3818, Anlotinib, Catequentinib) is a novel, orally administered, small molecule tyrosine kinase inhibitor. There remains an unmet need for effective, well tolerated therapies for patients (pts) with advanced/ metastatic leiomyosarcoma (LMS). We performed a randomized, double blind trial of Catequentinib monotherapy versus placebo in advanced/metastatic LMS. Methods: Patients with a diagnosis of LMS requiring third or further line treatment were eligible. Catequentinib was administered in a 21-day cycle with 14 days on and 7 days off regimen. In this double blind phase 3 trial, patients were randomized 2:1 to Catequentinib or placebo, with the option of crossover to Catequentinib after confirmed Progression Disease (PD) on placebo. Progression-free survival (PFS) with Log Rank test was the primary endpoint and the trial was conducted at multiple sites in the US, UK and EU. Results: Total N = 111 patients were enrolled, and N = 110 were treated and evaluated, 74 randomized to Catequentinib (C), and 36 to placebo (P). In arms (C)/(P) median ages were 59.0/60.5 (range: 33-91) years respectively and 59/29 (79.7%/80.6%) were female. Median PFS by Blinded Independent Central Review (BICR) met the primary endpoint at 3.42 months (95% CI: 2.60, 6.83) for (C) and 1.41 months (95% CI: 1.35, 4.86) for (P) with a p-value of 0.0265 and a HR of 0.536 (95% CI: 0.307, 0.936). Median PFS for patients stratified at ≤ 3 prior lines was 4.86 months (95% CI: 2.04, 8.94) for (C) and 1.41 months (95% CI: 1.31, 4.86) for (P) with a p-value of 0.0046 and a HR of 0.386 (95% CI: 0.196, 0.760). The 6-month progression-free rate was 42.37% for (C) and 20.71% for (P). OS was 17.45 months (95% CI: 13.57, 19.32) for (C) and 16.33 months (95% CI: 11.27, NE) for crossover patients in the (P) arm. 30 (40.5%) of patients have experienced grade 3 treatment-related adverse events in the (C) arm compared to 3 (8.3%) of patients in the (P) arm. The most common TEAE for (C) vs (P) were diarrhea (50.0% vs 22.2%), stomatitis (31.1% vs 8.3%), fatigue (64.9% vs 41.7%), and hypertension (47.3% vs 19.4%). Conclusions: This phase 3 trial met the primary PFS endpoint and demonstrates superior PFS for Catequentinib vs placebo in metastatic/advanced LMS. This study confirms the acceptable benefit-risk profile of Catequentinib in LMS. Catequentinib is an effective and well tolerated treatment option for patients with LMS. Clinical trial information: NCT03016819 .

In the INTRIGUE phase III trial (ClinicalTrials.gov identifier: NCT03673501 ), adult patients with advanced gastrointestinal stromal tumor previously treated with imatinib were randomly assigned 1:1 to ripretinib 150 mg once daily or sunitinib 50 mg once daily (4 weeks on/2 weeks off). In the primary analysis, overall survival (OS) was immature. In this study, we report the final planned analysis of OS (key secondary end point), progression-free survival (PFS) on third-line therapy (second PFS; prespecified exploratory end point), and long-term safety. Final OS analysis was prespecified to occur with approximately 200 and ≥145 events in the overall and KIT exon 11 intention-to-treat (ITT) populations, respectively. As of March 15, 2023, there were 211 and 151 OS events in the overall ITT and KIT exon 11 ITT populations, respectively. Median OS was similar between second-line ripretinib and sunitinib in both populations (overall, 35.5 v 31.5 months; KIT exon 11, 35.5 v 32.8 months). Median second PFS (on third-line therapy) for the overall ITT population was similar between the ripretinib and sunitinib arms (7.7 v 7.4 months). Safety was consistent with the primary analysis. OS from this analysis was similar between arms, and second PFS suggests that receiving ripretinib did not adversely affect the PFS of third-line therapy.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have become the first-line treatment of unresectable hepatocellular carcinoma (HCC). The prognostic value of immune-related adverse events (irAEs) in these patients remains controversial. We aimed to investigate the association between irAEs and clinical outcomes in patients with HCC treated with ICIs. METHODS: We searched the PubMed, Scopus, Web of Science, and Central Register of Controlled Trials databases for articles published from inception to June 2024, using keywords including ICI, HCC, and irAEs. Statistical analysis was performed with a random effects model. RESULTS: Of 3,028 studies, 24 (4,127 patients) met the criteria for inclusion. Atezolizumab plus bevacizumab was the most common treatment regimen (n = 10 studies). IrAEs were associated with an increased objective response rate (pooled relative ratio: 1.73; 95% confidence interval [CI]: 1.36–2.21, I 2 = 41%), a higher disease control rate (pooled relative ratio: 1.45; 95% CI: 1.21–1.74, I 2 = 74%), and longer progression-free survival (pooled hazard ratio [HR]: 0.66; 95% CI: 0.52–0.84, I 2 = 71%). There was a trend toward longer overall survival for patients with irAEs compared with those without (pooled HR: 0.84; 95% CI: 0.63–1.12, I 2 = 73%). Subgroup analysis indicated a survival benefit for patients with grade 1–2 irAEs (pooled HR: 0.50; 95% CI: 0.36–0.67, I 2 = 0%) and for those with endocrine irAEs (pooled HR: 0.63; 95% CI: 0.48–0.83, I 2 = 12%). DISCUSSION: The development of irAEs is associated with favorable clinical outcomes in HCC, including improved progression-free survival and higher objective response rate. Overall survival benefit was noted in patients with mild irAEs but not those with severe irAEs.