Citations

Introduction: Spontaneous coronary artery dissection (SCAD) is an understudied cause of acute myocardial infarction due to hematoma formation in coronary arteries primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Methods and Results: Through a meta-analysis of 8 GWAS (1917 cases, 9292 controls of European ancestry), we identified 17 risk loci, including 12 new. Functional annotations pointed at enrichment in enhancer marks of arteries, specifically smooth muscle cells, and strong candidate genes, such as tissue factor gene ( F3 ) on Chr1 near rs1146473 (OR=1.32, P=5.8 х10 -9 ). F3 is novel for SCAD or any cardiovascular disease. The risk allele correlated with F3 lower expression in arteries, supporting a mechanism consistent with hematoma formation. Bayesian gene regulatory networks constructed from expression and genetics data indicated the extracellular matrix organization in arteries as the biological function where most prioritized genes clustered (e.g. COL4A1/A2, HTRA1, and TIMP3 ). Overall, we report substantial polygenicity for SCAD (LDSC: h 2 SNP = 0.71 ± 0.11) and shared genetics with several neurovascular diseases (e.g intracranial aneurysm). Intriguingly, for 6 loci, colocalization analyses showed that SCAD and CAD are likely to share the same causal variants but involve opposite risk alleles (e.g COL4A1/A2 ). In addition, a negative genetic correlation was found between SCAD and CAD (rg=-0.12; P=3.7х10 -3 ), including after conditioning on BP (mt-COJO: rg CAD/SBP =-0.19, P=4.6х10 -6 ). Mendelian randomization analyses indicated higher BP to associate with increased risk for SCAD (beta IVW-SBP =0.05, P=7.6х10 -6 , beta IVW-DBP =0.10, P=1.9х10 -6 ) and CAD (beta IVW-SBP =0.04, P=8.6х10 -49 ; DBP: beta IVW-DBP =0.06, P=1.6х10 -44 ) but not BMI, lipids, or type 2 diabetes, which we confirmed as genetic risk factors for CAD Conclusions: Our results set the stage for future investigation of novel biological pathways relevant to both SCAD and CAD and potential therapeutic and preventive strategies specifically targeting this ischemic disease predominantly affecting women.

TPS8602 Background: Sarcomatoid mesothelioma is the most aggressive form of pleural mesothelioma and is associated with the worst prognosis of the histologic variants of this disease. In the Checkmate 743 clinical trial the patients with sarcomatoid mesothelioma who received ipilimumab and nivolumab had survival outcomes that were similar to those of patients with epithelioid mesothelioma. In comparison, the patients with sarcomatoid mesothelioma who received chemotherapy had the worst outcomes in this trial, highlighting the known limited efficacy of chemotherapy against this histologic variant. Checkmate 743 demonstrated that ipilimumab and nivolumab is a new standard of care for non-epithelioid mesothelioma. Surgery typically has not been offered to this group of patients given their historically poor outcomes. With the significant survival gains seen patients with sarcomatoid mesothelioma treated with immunotherapy, we hypothesized that surgery may extend the benefits seen with immunotherapy. Methods: Alliance for Clinical Trials in Oncology A082101 is a prospective, phase 2 nonrandomized clinical trial for patients with sarcomatoid mesothelioma. The co-primary objectives are to determine the percentage of patients with potentially resectable sarcomatoid mesothelioma able to proceed with surgery after neoadjuvant ipilimumab and nivolumab, and the progression-free survival (PFS) at 12 months (12-month PFS). For sample size determination, we assumed that if the true rate of surgery is 75% or greater, it would indicate that neoadjuvant immunotherapy is feasible to be given prior to surgery. On the other hand, if the true rate of surgery is 50% or less it would indicate that neoadjuvant immunotherapy is not worthy of further investigation. Twenty-six (26) eligible patients will be needed to receive neoadjuvant immunotherapy. If 16 or fewer of the 26 eligible patients proceed to surgery, it will be concluded that the experimental therapy is not worthy of further investigation. Otherwise, it will be concluded that the experimental therapy is worthy of further investigation. Safety monitoring will be done through a 6-week run-in for the first 10 patients to assess for pre-operative and post-operative toxicities and complications. Sequential boundaries will be used to monitor severe toxicity and complication rates. Accrual will be halted if excessive numbers of severe toxicity and complications in pre-operative and post-operative phases are seen. Tumor and blood-based biomarkers will be included as exploratory biomarkers. Clinical trial information: NCT05647265 .

4007 Background: Biliary tract cancer (BTC) is an aggressive malignancy with a poor prognosis, and current treatment options for advanced BTC are limited, with second-line therapy, FOLFOX and S-1 offering an objective response rate (ORR) of 5.0% and 7.5%, respectively. Up to 20% of BTCs overexpress human epidermal growth factor receptor 2 (HER2). Tucatinib (TUC) is a highly selective HER2-directed TKI approved for HER2-positive (HER2+) metastatic breast and colorectal cancer. Discussed here are the efficacy and safety results of TUC combined with Trastuzumab (Tras) in pts with previously treated HER2+ metastatic BTC. Methods: SGNTUC-019 (NCT04579380) is an open-label phase 2 basket study evaluating efficacy, safety, and tolerability of TUC and Tras in pts with HER2-altered solid tumors. Pts in the BTC cohort had been previously treated with and progressed after ≥1 line of systemic therapy for metastatic disease. Eligible pts had locally determined HER2+ (defined as HER2 overexpression determined by immunohistochemistry [IHC] 3+ or HER2 amplification determined by in situ hybridization assay or next-generation sequencing) metastatic BTC. Pts were treated on a 21-day cycle with TUC (300 mg orally twice a day) and Tras (8 mg/kg IV followed by 6 mg/kg every 3 wks). Disease status was determined based on RECIST v1.1 with assessments performed every 6 wks for 24 wks and every 12 wks thereafter. The primary endpoint is confirmed objective response rate (cORR) per investigator assessment. Secondary endpoints include overall survival (OS), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and safety. Results: Thirty pts were enrolled in the BTC cohort as of data cutoff date of 30 Nov 2022. The median duration of follow-up was 8.3 months. cORR was 46.7% (90% CI, 30.8, 63.0), with 14 responses including 1 complete and 13 partial responses. Median DOR was 6.0 months (90% CI, 5.5, not estimable). DCR was 76.7% (n=23; 90% CI, 60.6, 88.5), and median PFS was 5.5 months (90% CI, 3.9, 8.1). At data cutoff, 13 (43.3%) patients had died, and the 12-months OS rate was 53.8% (90% CI, 35.2, 69.1%). Overall, the most common treatment-emergent adverse events (TEAEs) reported were pyrexia (43.3%) and diarrhea (40.0%). Grade ≥3 TEAEs were reported in 18 (60.0%) of 30 pts; however, only 6 (20.0%) and 2 (6.7%) of these pts had Grade ≥3 TEAEs related to TUC and Tras, respectively. Two (6.7%) pts discontinued TUC due to TEAEs, cholangitis and liver disorder. No deaths were due to TEAEs. Conclusions: The combination of TUC and Tras was well tolerated in pts with previously treated HER2+ metastatic BTC. The observed antitumor activity supports the combination of TUC and Tras as a future chemotherapy-free treatment option for this population with historically poor outcomes. Clinical trial information: NCT04579380 .

2001 Background: Differentiating radiation necrosis from tumor progression remains one of the most commonly encountered and clinically challenging scenarios after radiation therapy (RT) for brain metastases (BM). PURSUE (NCT04410367) evaluated the diagnostic performance of 18F-fluciclovine, an amino acid PET radiopharmaceutical, based on various lesion metrics, to establish image interpretation criteria (IIC) for suspected recurrent BM after RT. Methods: Patients with solid tumor BM were enrolled across 7 US sites if they had a previously irradiated ‘reference’ lesion equivocal on MRI for recurrence and were planned for craniotomy. 18F-Fluciclovine PET (185 MBq) took place <42 days post-MRI and 1-21 days pre-craniotomy. The primary endpoint was the diagnostic performance (sensitivity, specificity, positive-, and negative-predictive value [PPV/NPV]) of different thresholds of lesion 18F-fluciclovine uptake on qualitative, visual reads vs central histopathological analysis. Lesion 18F-fluciclovine uptake was assessed qualitatively by 3 independent blinded readers who visually rated the uptake as ‘mild’ (up to blood pool), ‘moderate’ (above blood pool to parotid), or ‘marked’ (above parotid). Secondary endpoints included the diagnostic performance based on different thresholds of quantitative (e.g., lesion SUV) and dynamic measures of uptake. A committee, including 2 expert imaging physicians independent to PURSUE, reviewed all data in round-table meetings to establish the IIC, which were subsequently used to assess diagnostic performance. Results: All 23 reference lesions in 23 subjects underwent histopathological analysis, with 10 (43%) confirmed as recurrent tumor. The highest performing qualitative measure was ‘marked’, rendering a sensitivity of 92-100%, with variable specificity of 40-80% across readers. SUVmax was a reader-independent, high-performing quantitative metric on ROC analysis (AUC 0.87, SUVmax threshold 4.8 conferring a sensitivity of 80% and specificity of 85%). Dynamic measures did not provide added diagnostic value. After analyzing these metrics, the committee established IIC as: Lesions with 18F-fluciclovine uptake of a SUVmax equal to or greater than 4.8, or visually greater than the parotid gland, should be considered suspicious for recurrence. Otherwise, recurrence should be considered unlikely. Application of the IIC resulted in a sensitivity of 80%, specificity of 77-85%, PPV of 73-80%, and NPV of 83-85% across the readers. Conclusions: This is the first prospective multicenter trial to evaluate PET characteristics of suspected recurrent BM after RT, verified by histopathology. Qualitative and quantitative IIC show 18F-fluciclovine to be a high-performing diagnostic tool. These IIC will help evaluate the diagnostic performance of 18F-fluciclovine PET in future trials. Clinical trial information: NCT04410367 .

Abstract Background and purpose A heart age biomarker has been developed using deep neural networks applied to electrocardiograms. Whether this biomarker is associated with cognitive function was investigated. Methods Using 12‐lead electrocardiograms, heart age was estimated for a population‐based sample ( N = 7779, age 40–85 years, 45.3% men). Associations between heart delta age (HDA) and cognitive test scores were studied adjusted for cardiovascular risk factors. In addition, the relationship between HDA, brain delta age (BDA) and cognitive test scores was investigated in mediation analysis. Results Significant associations between HDA and the Word test, Digit Symbol Coding Test and tapping test scores were found. HDA was correlated with BDA (Pearson's r = 0.12, p = 0.0001). Moreover, 13% (95% confidence interval 3–36) of the HDA effect on the tapping test score was mediated through BDA. Discussion Heart delta age, representing the cumulative effects of life‐long exposures, was associated with brain age. HDA was associated with cognitive function that was minimally explained through BDA.

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): UiT The Arctic University of Norway, Northern Norway Regional Health Authority. Background/Introduction Machine learning models have been applied to magnetic resonance images of the brain to estimate brain age gap as a biomarker of biological aging. Because of its association with cognitive performance and neurological disorders, brain age gap has become an indicator of general brain health. Among others, cardiovascular risk factors are associated with brain health. Recently a novel non-invasive biomarker of vascular ageing has been proposed based on the application of a deep-learning algorithm to digitised 12-lead electrocardiograms. The difference between electrocardiogram predicted age and chronological age is defined as vascular age gap and has been shown to be associated with an adverse cardiovascular profile. However, the association of vascular age gap with cognitive health and dementias has not yet been examined. Purpose We apply a causal mediation framework to vascular age gap, brain age gap and cognitive function data obtained in the same individuals who took part in a population-based study in Norway. We hypothesise that cardiovascular risk factors encapsulated in vascular age gap can indirectly affect cognitive function by increasing the brain age gap. Methods We applied a deep learning algorithm (1) to electrocardiograms (N=7779, age 40-85 years) collected from the population-based sample in Norway (mean age 63.8 years, 45.3% men) to obtain a vascular age gap. For a subsample (N=1693) magnetic resonance images of the brain were also available and another deep neural network algorithm (2) was applied to obtain a biomarker of brain age. For 1678 participants with both vascular age gap and brain age gap available we used mediation analysis to test whether brain age gap mediates the effects of vascular age gap on cognitive function (as measured by mini mental status test, word memory test, digit–symbol coding test, tapping test) by estimating total, direct and indirect effects. Results We found a weak correlation (Pearson’s r = 0.12) between vascular age gap and brain age gap. Both age gaps were associated with cognitive scores capturing psychomotor speed, attention and mental flexibility. For a 1 standard deviation (7.3 years) increase in vascular age gap digit-symbol coding test score decreased by 0.63 (95%CI: -0.89, -0.36; p&lt;0.001) points, and tapping test decreased by 0.36 (95%CI: -0.56, -0.14; p=0.001). Only 13% of effect of vascular age gap on cognitive test results was mediated by brain age gap. Conclusion(s) Vascular age gap was weakly associated with poorer cognitive functioning, and only 13% of this association was mediated by brain age gap. This suggests that cognitive decline linked to accumulated damage of the vascular system is not fully captured by structural changes in the brain. Further investigations of novel measures of biological aging in relation to cognitive decline are warranted as these may hold promise for improved understanding of mechanisms and clinical prediction.

The prevalence of atrial fibrillation (AF) is forecasted to increase manifold, emphasizing the need for efficacious treatments. Pulmonary vein isolation (PVI) to eliminate ectopic triggers is now established as a fundamental component of the invasive treatment of AF, however its efficacy in persistent AF remains suboptimal. The atrial myocardium undergoes adverse fibrotic remodeling as AF progresses, favoring arrhythmia initiation and maintenance. Reductions in left atrial bipolar voltage have been suggested to identify regions of such pathological remodeling, and represent novel targets for ablation to target the arrhythmogenic substrate. Early observational studies targeting these low voltage areas (LVA) have been encouraging, however results from more recent randomized trials are more mixed. Importantly, there is significant heterogeneity in the techniques for identifying LVAs and the strategies for ablation. In reality, the atrial arrhythmogenic substrate is multi-faceted rather than being limited to fibrosis and there remains uncertainty as to how accurately LVAs represent regions of fibrosis. Additionally, bipolar voltage is influenced by numerous physiological and biophysical factors. The present review summarizes the current evidence for LVA ablation in AF. We then analyze the components of the atrial arrhythmic substrate, its relationship to LVAs and the limitations in LVA assessment. Finally we discuss novel techniques for delineating the atrial substrate.

AbstractThis meta‐analysis investigated the effects of exercise on Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) scores following vertebroplasty or kyphoplasty in osteoporotic fractures. A literature search of PubMed, EMBASE (Elsevier), CiNAHL, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Scopus, and Web of Science was conducted from database inception to October 6, 2022. Eligible studies reported osteoporosis patients over 18 years of age with a diagnosis of at least one vertebral fracture via radiography or clinical assessment. This review was registered in PROSPERO (ID: CRD42022340791). Ten studies met the eligibility criteria (n = 889). VAS scores at baseline were 7.75 (95% CI: 7.54, 7.97, I2 = 76.11%). Following initiation of exercise, VAS scores at the endpoint of 12 months were 1.91 (95% CI: 1.53, 2.29, I2 = 92.69%). ODI scores at baseline were 68.66 (95% CI: 56.19, 81.13, I2 = 85%). Following initiation of exercise, ODI scores at the endpoint of 12 months were 21.20 (95% CI: 14.52, 27.87, I2 = 99.30). A two‐arm analysis demonstrated improved VAS and ODI for the exercise group compared to non‐exercise control at 6 months (MD = −0.70, 95% CI: −1.08, −0.32, I2 = 87% and MD = −6.48, 95% CI: −7.52, −5.44, I2 = 46%, respectively) and 12 months (MD = −0.88, 95% CI: −1.27, −0.49, I2 = 85% and MD = −9.62, 95% CI: −13.24, −5.99, I2 = 93%). Refracture was the only adverse event reported and occurred almost twice as frequently in the non‐exercise group than in the exercise group. Exercise rehabilitation post vertebral augmentation is associated with improved pain and functionality, particularly after 6 months of exposure, and may reduce refracture rate.

Accurate prediction of progression in subjects at risk of Alzheimer's disease is crucial for enrolling the right subjects in clinical trials. However, a prospective comparison of state-of-the-art algorithms for predicting disease onset and progression is currently lacking. We present the findings of "The Alzheimer's Disease Prediction Of Longitudinal Evolution" (TADPOLE) Challenge, which compared the performance of 92 algorithms from 33 international teams at predicting the future trajectory of 219 individuals at risk of Alzheimer's disease. Challenge participants were required to make a prediction, for each month of a 5-year future time period, of three key outcomes: clinical diagnosis, Alzheimer's Disease Assessment Scale Cognitive Subdomain (ADAS-Cog13), and total volume of the ventricles. The methods used by challenge participants included multivariate linear regression, machine learning methods such as support vector machines and deep neural networks, as well as disease progression models. No single submission was best at predicting all three outcomes. For clinical diagnosis and ventricle volume prediction, the best algorithms strongly outperform simple baselines in predictive ability. However, for ADAS-Cog13 no single submitted prediction method was significantly better than random guesswork. Two ensemble methods based on taking the mean and median over all predictions, obtained top scores on almost all tasks. Better than average performance at diagnosis prediction was generally associated with the additional inclusion of features from cerebrospinal fluid (CSF) samples and diffusion tensor imaging (DTI). On the other hand, better performance at ventricle volume prediction was associated with inclusion of summary statistics, such as the slope or maxima/minima of patient-specific biomarkers. On a limited, cross-sectional subset of the data emulating clinical trials, performance of the best algorithms at predicting clinical diagnosis decreased only slightly (2 percentage points) compared to the full longitudinal dataset. The submission system remains open via the website https://tadpole.grand-challenge.org, while TADPOLE SHARE (https://tadpole-share.github.io/) collates code for submissions. TADPOLE's unique results suggest that current prediction algorithms provide sufficient accuracy to exploit biomarkers related to clinical diagnosis and ventricle volume, for cohort refinement in clinical trials for Alzheimer's disease. However, results call into question the usage of cognitive test scores for patient selection and as a primary endpoint in clinical trials.