Leiner, Tim

AbstractBackgroundPeripheral arterial disease (PAD) is a chronic occlusive disease that restricts blood flow in the lower limbs, causing partial or complete blockages of the blood flow. While digital subtraction angiography (DSA) has traditionally been the preferred method for assessing blood flow in the lower limbs, advancements in wide beam Computed Tomography (CT), allowing successive acquisition at high frame rate, might enable hemodynamic measurements.PurposeTo quantify the arterial blood flow in stenotic below‐the‐knee (BTK) arteries. To this end, we propose a novel method for contrast bolus tracking and assessment of quantitative hemodynamic parameters in stenotic arteries using 4D‐CT.MethodsFifty patients with suspected PAD underwent 4D‐CT angiography in addition to the clinical run‐off computed tomography angiography (CTA). From these dynamic acquisitions, the BTK arteries were segmented and the region of maximum blood flow was extracted. Time attenuation curves (TAC) were estimated using 2D spatio‐temporal B‐spline regression, enforcing both spatial and temporal smoothness. From these curves, quantitative hemodynamic parameters, describing the shape of the propagating contrast bolus were automatically extracted. We evaluated the robustness of the proposed TAC fitting method with respect to interphase delay and imaging noise and compared it to commonly used approaches. Finally, to illustrate the potential value of 4D‐CT, we assessed the correlation between the obtained hemodynamic parameters and the presence of PAD.Results280 out of 292 arteries were successfully segmented, with failures mainly due to a delayed contrast arrival. The proposed method led to physiologically plausible hemodynamic parameters and was significantly more robust compared to 1D temporal regression. A significant correlation between the presence of proximal stenoses and several hemodynamic parameters was found.ConclusionsThe proposed method based on spatio‐temporal bolus tracking was shown to lead to stable and physiologically plausible estimation of quantitative hemodynamic parameters, even in the case of stenotic arteries. These parameters may provide valuable information in the evaluation of PAD and contribute to its diagnosis.

AbstractSince the introduction of BRAF(/MEK) inhibition and immune checkpoint inhibition (ICI), the prognosis of advanced melanoma has greatly improved. Melanoma is known for its remarkably long time to first distant recurrence (TFDR), which can be decades in some patients and is partly attributed to immune‐surveillance. We investigated the relationship between TFDR and patient outcomes after systemic treatment for advanced melanoma. We selected patients undergoing first‐line systemic therapy for advanced melanoma from the nationwide Dutch Melanoma Treatment Registry. The association between TFDR and progression‐free survival (PFS) and overall survival (OS) was assessed by Cox proportional hazard regression models. The TFDR was modeled categorically, linearly, and flexibly using restricted cubic splines. Patients received anti‐PD‐1‐based treatment (n = 1844) or BRAF(/MEK) inhibition (n = 1618). For ICI‐treated patients with a TFDR <2 years, median OS was 25.0 months, compared to 37.3 months for a TFDR >5 years (P = .014). Patients treated with BRAF(/MEK) inhibition with a longer TFDR also had a significantly longer median OS (8.6 months for TFDR <2 years compared to 11.1 months for >5 years, P = .004). The hazard of dying rapidly decreased with increasing TFDR until approximately 5 years (HR 0.87), after which the hazard of dying further decreased with increasing TFDR, but less strongly (HR 0.82 for a TFDR of 10 years and HR 0.79 for a TFDR of 15 years). Results were similar when stratifying for type of treatment. Advanced melanoma patients with longer TFDR have a prolonged PFS and OS, irrespective of being treated with first‐line ICI or targeted therapy.

Abstract Objectives To assess the diagnostic performance of CT-FFR for the diagnosis of CAD in the work-up for TAVI. Background Work-up for transcatheter aortic valve implantation (TAVI) currently utilizes computed tomography (CT) to evaluate annulus diameter and peripheral vascular access, plus invasive coronary angiography (ICA) to assess significant coronary artery disease (CAD). ICA might partially be redundant with the use of Coronary CT Angiography (CCTA). Prior studies found improvement of the diagnostic accuracy of CCTA by use of CT derived fractional flow reserve (CT-FFR). Methods Consecutive patients with severe symptomatic aortic valve stenosis who underwent TAVI work-up between 2015–2019 were included in this cross-sectional study. All patients underwent CCTA and ICA within 3 months and diagnostic performance of both CCTA and CT-FFR were assessed using ICA as reference. Results Seventy-six of the 338 patients included in the analysis had ≥1 significant coronary stenosis at ICA. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy per-patient were 76.9%, 64.5%, 34.0%, 92.1% and 66.9% for CCTA and 84.6%, 88.3%, 63.2%, 96.0% and 87.6% for CT-FFR. The area under the receiver-operating characteristic-curve significantly differ between CCTA and CT-FFR (0.84 versus 0.90 p=0.02). A CT-FFR guided approach could avoid ICA in 57.1% versus 43.6% using CCTA. Conclusions CT-FFR significantly improves the diagnostic accuracy of CCTA without additional testing and increases the proportion of patients in whom ICA could have been safely avoided It has the potential to be integrated in the current clinical work-up for TAVI for diagnosing stable CAD requiring treatment. Funding Acknowledgement Type of funding sources: None.

Abstract Background Coronary artery calcium (CAC) scoring improves event prediction of coronary heart disease (CHD) and can be used to guide initiation or deferral of statin therapy in asymptomatic individuals at low-to-intermediate risk. However, there is substantial variation of CAC scores acquired with different CT scanners. Therefore, CAC scoring discrepancies may lead to suboptimal patients' treatment and harmonization is needed. Purpose The aim of our study was twofold. Our first aim was to develop a calibration tool resulting in vendor neutral Agatston Score (vnAS). Second, we aimed to assess the effect of using this calibration tool in the existing Multi-Ethnic Study of Atherosclerosis (MESA) study cohort on both risk prediction of coronary heart disease (CHD), and initiation of statin therapy. Methods Two static anthropomorphic phantoms containing multiple CAC inserts were imaged on seven different CT systems and one EBT system. For each CT system, the vnAS calculator parameters were derived using regression analysis based on Agatston scores from EBT and CT. To validate our vnAS, we used CAC scoring information and clinical data of participants from MESA study. All included participants (Cohort I, n=3181) were assigned to one out of four calcium groups, which were defined as zero-calcium (AS and vnAS of 0), low-calcium (AS and vnAS of 1–99) high-calcium (AS and vnAS ≥100), and reclassified individuals (AS &lt;100 and vnAS ≥100). The occurrence of CHD events in each group was assessed and multivariable Cox regression models were used to assess the added value of the vnAS in the prediction of CHD events For a sub-cohort of 890 participants at intermediate cardiovascular risk, the potential benefit from statin therapy was estimated based on the number needed to treat (NNT). NNT were determined for patients with vnAS ≥100 and vnAS ≥300 with original AS below 100 (group I) or 300 (group II), respectively. Results For all CT systems, a high degree of correlation with EBT Agatston scores was shown (R2 &gt;0.932). Using the vnAS, 85 individuals (2.7%) were reclassified from a lower to a higher risk category. For the reclassified participants, CHD event rates increased significantly from 7% to 15% (p=0.008) with a CHD hazard ratio of 3.39 (95% CI 1.82–6.35, p=0.001) (Figure 1). In intermediate risk cohort, the NNT was smaller for reclassified individuals as compared to their original (low) calcium group, at 7 vs 12 for group I and 2 vs 15 for group II, respectively. The summary of vnAS applicability is depicted in Figure 2. Conclusions We developed a calibration tool, which enables to calculate vendor neutral AS (vnAS). Based on vnAS, 85 individuals from MESA study, who were reclassified from a lower to a higher calcium category, did indeed have a higher CHD event rate. Consequently, the potential benefit from statin therapy, based on vnAS, was also increased for reclassified participants at intermediate cardiovascular risk. Funding Acknowledgement Type of funding sources: None.

The prognostic value of CT-derived muscle quantity for overall survival (OS) in patients with non-small-cell lung cancer (NSCLC) is uncertain due to conflicting evidence. We hypothesize that increased muscle quantity is associated with better OS in patients with normal muscle radiodensity but not in patients with fatty degeneration of muscle tissue and low muscle radiodensity. We performed an observational cohort study in NSCLC patients treated with radiotherapy. A deep learning algorithm was used to measure muscle quantity as psoas muscle index (PMI) and psoas muscle radiodensity (PMD) on computed tomography. The potential interaction between PMI and PMD for OS was investigated using Cox proportional-hazards regression. Baseline adjustment variables were age, sex, histology, performance score and body mass index. We investigated non-linear effects of continuous variables and imputed missing values using multiple imputation. We included 2840 patients and observed 1975 deaths in 5903 patient years. The average age was 68.9 years (standard deviation 10.4, range 32 to 96) and 1692 patients (59.6%) were male. PMI was more positively associated with OS for higher values of PMD (hazard ratio for interaction 0.915; 95% confidence interval 0.861–0.972; p-value 0.004). We found evidence that high muscle quantity is associated with better OS when muscle radiodensity is higher, in a large cohort of NSCLC patients treated with radiotherapy. Future studies on the association between muscle status and OS should accommodate this interaction in their analysis for more accurate and more generalizable results.

Background Adolescents with chronic disease are often exposed to inflammatory, metabolic, and hemodynamic risk factors for early atherosclerosis. Since postmortem studies have shown that atherogenesis starts in the aorta, the CDACD (Cardiovascular Disease in Adolescents with Chronic Disease) study investigated preclinical aortic atherosclerosis in these adolescents. Methods and Results The cross‐sectional CDACD study enrolled 114 adolescents 12 to 18 years old with chronic disorders including juvenile idiopathic arthritis, cystic fibrosis, obesity, corrected coarctation of the aorta, and healthy controls with a corrected atrial septal defect. Cardiovascular magnetic resonance was used to assess aortic pulse wave velocity and aortic wall thickness, as established aortic measures of preclinical atherosclerosis. Cardiovascular magnetic resonance showed a higher aortic pulse wave velocity, which reflects aortic stiffness, and higher aortic wall thickness in all adolescent chronic disease groups, compared with controls ( P <0.05). Age (β=0.253), heart rate (β=0.236), systolic blood pressure (β=−0.264), and diastolic blood pressure (β=0.365) were identified as significant predictors for aortic pulse wave velocity, using multivariable linear regression analysis. Aortic wall thickness was predicted by body mass index (β=0.248) and fasting glucose (β=0.242), next to aortic lumen area (β=0.340). Carotid intima‐media thickness was assessed using ultrasonography, and was only higher in adolescents with coarctation of the aorta, compared with controls ( P <0.001). Conclusions Adolescents with chronic disease showed enhanced aortic stiffness and wall thickness compared with controls. The enhanced aortic pulse wave velocity and aortic wall thickness in adolescents with chronic disease could indicate accelerated atherogenesis. Our findings underscore the importance of the aorta for assessment of early atherosclerosis, and the need for tailored cardiovascular follow‐up of children with chronic disease.

12081 Background: A common conception is that exercise training is cardioprotective for patients with breast cancer receiving adjuvant chemotherapy, but evidence to support this assertion is limited. This study aims to evaluate the effect of exercise training during adjuvant chemotherapy for breast cancer on long-term structural and functional cardiac outcomes. Methods: This is a follow-up study of two previously performed randomized studies in breast cancer patients; the PACT (N = 204) and PACES (N = 230) study. Cardiac outcomes, including extracellular volume fraction (ECV), left ventricular ejection fraction (LVEF) on cardiac MRI and global longitudinal strain (GLS) on echocardiography, were evaluated in patients allocated to moderate-to high-intensity exercise and non-exercise controls using linear and logistic regression models, adjusted for relevant confounders. Additionally, we explored the influence of self-reported PA during chemotherapy on cardiac outcomes, regardless of treatment allocation. Results: In total, 185 breast cancer survivors were included (mean age 58.9±7.8 years, mean time since treatment 8.5±1.1 years). Mean ECV was 25.3±2.5 in the control group and 24.6±2.8 in the exercise group. Mean LVEF was borderline normal in both (54.6±4.9 and 53.0±7.8) with an LVEF < 50% of 17.1% and 27.8% in control and exercise group, respectively. Compared to control, no significant effect of exercise during chemotherapy on ECV (β = -0.61, 95%CI: -1.55;0.32) or on abnormal ECV (OR = 0.80, 95%CI: 0.26;2.45) was found. Native T1 was statistically significantly lower in the exercise group compared to control (β = -16.75%CI: -31.5 ;-1.93). The odds of having an abnormal native T1 appeared lower in the exercise group (OR 0.58, 95%CI: 0.28;1.17). We found no benefit of exercise for LVEF or GLS (β = -1.82, 95%CI: -4.06;0.42 and β = 0.21, 95%CI: -0.87;1.28), nor on the likelihood of having an abnormal LVEF or GLS (OR = 1.78, 95%CI: 0.79;4.16); OR = 1.21, 95%CI: 0.56;2.63), respectively. Higher self-reported physical activity levels during chemotherapy tended to be associated with better cardiac outcomes. Conclusions: Exercise training during chemotherapy was not associated with long-term cardioprotection in patients with early-stage breast cancer. The high prevalence of cardiac abnormalities years post-chemotherapy suggests the need to include cardiac assessment in long-term follow-up programs for breast cancer survivors and calls for more research on cardioprotective measures during adjuvant chemotherapy, including alternative exercise dosing regimens and pharmacological adjuncts. Clinical trial information: NTR7247.

AbstractIron overload is a severe general complication of hereditary anemias. Treatment with iron chelators is hampered by important side‐effects, high costs, and the lack of availability in many countries with a high prevalence of hereditary anemias. In this phase III randomized placebo‐controlled trial, we assigned adults with non‐transfusion‐dependent hereditary anemias with mild‐to‐moderate iron overload to receive esomeprazole (at a dose of 40 mg twice daily) or placebo for 12 months in a cross‐over design. The primary end point was change of liver iron content measured by MRI. A total of 30 participants were enrolled in the trial. Treatment with esomeprazole resulted in a statistically significant reduction in liver iron content that was 0.55 mg Fe/g dw larger than after treatment with placebo (95%CI [0.05 to 1.06]; p = 0.03). Median baseline liver iron content at the start of esomeprazole was 4.99 versus 4.49 mg Fe/g dw at start of placebo. Mean delta liver iron content after esomeprazole treatment was −0.57 (SD 1.20) versus −0.11 mg Fe/g dw (SD 0.75) after placebo treatment. Esomeprazole was well tolerated, reported adverse events were mild and none of the patients withdrew from the study due to side effects. In summary, esomeprazole resulted in a significant reduction in liver iron content when compared to placebo in a heterogeneous group of patients with non‐transfusion‐dependent hereditary anemias. From an international perspective this result can have major implications given the fact that proton pump inhibitors may frequently be the only realistic therapy for many patients without access to or not tolerating iron chelators.