Predicting response to pembrolizumab in metastatic melanoma by a new personalization algorithm.

BACKGROUND: At present, immune checkpoint inhibitors, such as pembrolizumab, are widely used in the therapy of advanced non-resectable melanoma, as they induce more durable responses than other available treatments. However, the overall response rate does not exceed 50% and, considering the high costs and low life expectancy of nonresponding patients, there is a need to select potential responders before therapy. Our aim was to develop a new personalization algorithm which could be beneficial in the clinical setting for predicting time to disease progression under pembrolizumab treatment. METHODS: We developed a simple mathematical model for the interactions of an advanced melanoma tumor with both the immune system and the immunotherapy drug, pembrolizumab. We implemented the model in an algorithm which, in conjunction with clinical pretreatment data, enables prediction of the personal patient response to the drug. To develop the algorithm, we retrospectively collected clinical data of 54 patients with advanced melanoma, who had been treated by pembrolizumab, and correlated personal pretreatment measurements to the mathematical model parameters. Using the algorithm together with the longitudinal tumor burden of each patient, we identified the personal mathematical models, and simulated them to predict the patient's time to progression. We validated the prediction capacity of the algorithm by the Leave-One-Out cross-validation methodology. RESULTS: Among the analyzed clinical parameters, the baseline tumor load, the Breslow tumor thickness, and the status of nodular melanoma were significantly correlated with the activation rate of CD8+ T cells and the net tumor growth rate. Using the measurements of these correlates to personalize the mathematical model, we predicted the time to progression of individual patients (Cohen's κ = 0.489). Comparison of the predicted and the clinical time to progression in patients progressing during the follow-up period showed moderate accuracy (R2 = 0.505). CONCLUSIONS: Our results show for the first time that a relatively simple mathematical mechanistic model, implemented in a personalization algorithm, can be personalized by clinical data, evaluated before immunotherapy onset. The algorithm, currently yielding moderately accurate predictions of individual patients' response to pembrolizumab, can be improved by training on a larger number of patients. Algorithm validation by an independent clinical dataset will enable its use as a tool for treatment personalization.

Assessment of peri-device leaks after interventional left atrial appendage closure using standardized imaging by cardiac computed tomography angiography.

Cardiac computed tomography angiography (cCTA) has recently been proposed for evaluation of successful interventional left atrial appendage closure (LAA/LAAC). This prospective longitudinal observational study aims to assess this proposal by applying a standardized imaging protocol to detect and quantify peri-device leaks (PDL) after LAAC. cCTA datasets of consecutive patients 6 months after successful LAAC were acquired on a third generation dual-source computed tomography system and reconstructed with a slice thickness of 0.5 mm. The standardized multi-planar reconstruction LAA occluder view for post-implantation evaluation (LOVE) algorithm was used to assess PDL in relation to LAA morphology and implanted LAAC devices. A total of 49 patients (median age 80 years, 24% female) were included consecutively. Overall PDL rate was 31%. Leak rates among different left atrial appendage morphologies varied largely. Windsock type had the highest incidence of PDL (47%). AMPLATZER™ AMULET™ device type revealed slightly higher PDL rates than WATCHMAN™ type and showed larger leaks. However, no statistical differences were found. PDL can be sized best in LOVE sagittal views, whereas a synopsis of LOVE sagittal, axial and coronal views allows further examination and detection of small leaks. PDL are common after successful interventional LAAC, which can be accurately detected and sized by standardized cCTA imaging protocols.

Relation of left atrial appendage closure devices to topographic neighboring structures using standardized imaging by cardiac computed tomography angiography.

BACKGROUND: Although left atrial appendage (LAA) anatomy and topographic relations are well understood, little is known about the impairment of neighboring structures (NBS) by an implanted left atrial appendage closure (LAAC) device. This prospective longitudinal observational study for the first time describes distances of implanted LAA closure (LAAC) devices to NBS using a standardized imaging protocol of cardiac computed tomography angiography (cCTA). HYPOTHESIS: cCTA imaging is an eligible tool for post-implantation evaluation of LAAC devices and their relation to neighboring structures. METHODS: cCTA data sets of consecutive patients 6 months after successful LAAC were acquired on a third generation dual-source CT system and reconstructed with a slice thickness of 0.5 mm. The standardized multi-planar reconstruction LAA occluder view for post-implantation evaluation (LOVE) algorithm was used to measure the distances to NBS in relation to LAA morphology and implanted LAAC devices. RESULTS: A total of 48 patients (median age 80 years, 25% female) were included. Left upper pulmonary vein and circumflex artery were generally closest to occlusion devices (median 2.9 and 2.8 mm, respectively). AMPLATZER AMULET devices were closer to the mitral valve annulus than WATCHMAN devices (6.6 mm (inter quartile range [IQR] 4.9-8.6) vs 10.9 mm (IQR 7.4-14.0), P = 0.001). Distances to the left upper pulmonary vein were affected by LAA morphology, with cauliflower type having the closest proximity (1.7 mm [IQR 1.0-3.4], P = 0.048). CONCLUSION: A standardized cCTA imaging protocol is an eligible tool to accurately measure distances to NBS. Left upper pulmonary vein and circumflex artery are closest to LAAC devices and could thus be most prone to impairment.

Time to Exhale: Additional Value of Expiratory Chest CT in Chronic Obstructive Pulmonary Disease.

Objectives: Diagnostic guidelines for chronic obstructive pulmonary disease (COPD) are based on spirometry and clinical criteria. However, this does not address the pathophysiological complexity of the disease sufficiently. Until now, inspiratory chest computed tomography (CT) has been considered as the preferred imaging method in these patients. We hypothesized that expiratory CT may be superior to demonstrate pathophysiological changes. The aim of this prospective study was to systematically compare lung function tests with quantified CT parameters in inspiration and expiration. Materials and Methods: Forty-six patients with diagnosed COPD underwent spirometry, body plethysmography, and dose-optimized CT in maximal inspiration and expiration. Four quantified CT parameters were acquired in inspiration, expiration, and their calculated delta values. These parameters were correlated with seven established lung function parameters. Results: For inspiratory scans, a weak-to-moderate correlation with the lung function parameters was found. These correlations significantly improved when adding the expiratory scan (p < 0.05). Moreover, some parameters showed a significant correlation only in expiratory datasets. Calculated delta values showed even stronger correlation with lung function testing. Conclusions: Expiratory quantified CT and calculated delta values significantly improve the correlation with lung function parameters. Thus, an additional expiratory CT may improve image-based phenotyping of patients with COPD.

[18F]-Fluorodeoxyglucose-Positron Emission Tomography in Rats with Prolonged Cocaine Self-Administration Suggests Potential Brain Biomarkers for Addictive Behavior.

The DSM5-based dimensional diagnostic approach defines substance use disorders on a continuum from recreational drug use to habitual and ultimately addicted behavior. Biomarkers that are indicative of recreational drug use and addicted behavior are lacking. We performed a translational [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) study in the multi-dimensional 0/3crit model of cocaine addiction. Addict-like (3crit) and non-addict-like (0crit) rats, which shared identical life conditions and levels of cocaine self-administration, were acquired for FDG-PET under baseline conditions and following cocaine and yohimbine challenges. Compared to cocaine-naïve control rats, 0crit animals showed higher glucose uptake in the caudate putamen (CPu) and medial prefrontal cortex (mPFC) respect to naïve controls. 3crit animals did not show this adaptive higher glucose utilization, but had lower uptake in several cortical areas. Both cocaine and yohimbine challenges affected glucose uptake in control rats in several brain sites, but not in 0crit and 3crit rats, indicating that impaired glucose mobilization in response to these challenges is not specifically associated with addictive behavior. Compared to 0crit, 3crit rats showed higher reinstatement responses, which were negatively associated with glucose uptake in the ventral tegmental area. Data indicate that cocaine non-addict- and addict-like phenotypes are associated with several potential biomarkers. Specifically, we propose that increased glucose uptake in the CPu and mPFC is a function of controlled drug use, whereas a loss of striatal and prefrontal metabolic activity and reduced uptake in cortical areas are indicative of addictive behavior.

Clinical Impact of Rest Dual-energy Computed Tomography Myocardial Perfusion in Patients with Coronary Artery Disease.

BACKGROUND/AIM: To evaluate the hypothesis that patients with suspected coronary artery disease (CAD) assessed using rest dual-energy computed tomography-derived myocardial perfusion imaging (DECT-P), could have fewer invasive coronary angiographies (ICA), showing non-obstructive CAD. MATERIALS AND METHODS: Patients who had undergone coronary computed tomography angiography (cCTA), rest DECT-P and ICA were analyzed. RESULTS: We evaluated 51 patients (62.7% males, mean age 51.6±12.8 years). Rest DECT-P identified perfusion defects in three (10.7%) of the 28 patients with cCTA negative for luminal stenosis and in 10 (43.5%) of the 23 patients with cCTA positive for luminal stenosis. In total, 21 patients underwent both cCTA and ICA, of which seven (33.3%) showed obstructive CAD. Rest DECT-P revealed false-negative results in four cases (19.1%) and false-positive results in six cases (28.6%). CONCLUSION: Adding rest DECT-P to cCTA has no incremental diagnostic value over cCTA alone, to exclude haemodynamically significant CAD. Therefore, a rest-stress-DECT-P protocol or a CT-based FFR calculation might be a promising concept to improve diagnostic accuracy in a real clinical setting.

Comparative analysis of high-sensitivity cardiac troponin I and T for their association with coronary computed tomography-assessed calcium scoring represented by the Agatston score.

BACKGROUND: This study evaluates the association between high-sensitivity cardiac troponin I (hs-cTnI) and T (hs-cTnT) and coronary calcium concentration (CAC) detected by coronary computed tomography (CCT) and evaluated with the Agatston score in patients with suspected coronary artery disease (CAD). METHODS: Patients undergoing CCT during routine clinical care were enrolled prospectively. CCT was indicated for patients with a low to intermediate pretest probability for CAD. Within 24 h of CCT examination, peripheral blood samples were taken to measure cardiac biomarkers hs-cTnI and hs-cTnT. RESULTS: A total of 76 patients were enrolled including 38% without detectable CAC, 36% with an Agatston score from 1 to 100, 17% from 101 to 400, and 9% with values ≥ 400. hs-cTnI was increasing alongside Agatston score and was able to differentiate between different groups of Agatston scores. Both hs-cTn discriminated values greater than 100 (hs-cTnI, AUC = 0.663; p = 0.032; hs-cTnT, AUC = 0.650; p = 0.048). In univariate and multivariate logistic regression models, hs-cTnT and hs-cTnI were significantly associated with increased Agatston scores. Patients with hs-cTnT ≥ 0.02 µg/l and hs-cTnI ≥ 5.5 ng/l were more likely to reveal values ≥ 400 (hs-cTnT; OR = 13.4; 95% CI 1.545-116.233; p = 0.019; hs-cTnI; OR = 8.8; 95% CI 1.183-65.475; p = 0.034). CONCLUSION: The present study shows that the Agatston score was significantly correlated with hs cardiac troponins, both in univariable and multivariable linear regression models. Hs-cTnI is able to discriminate between different Agatston values. The present results might reveal potential cut-off values for hs cardiac troponins regarding different Agatston values. Trial registration Cardiovascular Imaging and Biomarker Analyses (CIBER), NCT03074253 https://clinicaltrials.gov/ct2/show/record/NCT03074253.

Low dose time-resolved CT-angiography in pediatric patients with venous malformations using 3rd generation dual-source CT: Initial experience.

OBJECTIVES: To prospectively evaluate the diagnostic value and radiation dose of time-resolved CT-Angiography (4D-CTA) in pediatric patients with venous malformations using 3rd generation dual-source CT (DSCT) at 70 kVp tube voltage. METHODS: Between November 2014 and August 2015, seven children (2 male, 5 female; median age, 9 years; range 3-12 years) with suspected peripheral, non-cerebral, venous malformations were included in this feasibility study and underwent US, MRI and 4D-CTA. All three imaging modalities were analyzed and compared individually by an experienced interventional radiologist and a pediatric surgeon using a 5-point Likert scale, with regard to diagnosis of the vascular anomaly, additional information like presence of thrombophlebitis and lesion extension, flow dynamics, localization, volume and significance for treatment planning. For quantitative statistical analysis, an unifactorial analysis of variance was performed for every parameter and all three imaging modalities. Radiation dose values as expressed by the volume CT dose index (CTDIvol) and dose-length product (DLP) were recorded for of all patients. RESULTS: Three out of six patients had isolated type I venous malformations without peripheral venous drainage which could be demonstrated on MRI and CT. In two out of six patients a type II venous malformation with drainage into normal veins was diagnosed. In one case, 4D-CT was the only imaging modality that revealed a slow-flow venous malformation with shunting supply by a hypodynamic arterial feeder. TREATMENT PLANNING: 4D-CTA was rated as the best imaging modality for treatment planning with agreement between radiologist and surgeon, especially with respect to the hemodynamics of the venous malformation. CONCLUSIONS: 4D-CTA at 70 kVp is a fast imaging modality that provides comprehensive diagnostic information of venous malformations in pediatric patients and is very valuable for therapy planning. Radiation dose of 4D-CTA must be weighted against the diagnostic information as well as the potential risk for sedation and contrast administration during MRI.

In Vivo Evaluation of ¹8F-SiFAlin-Modified TATE: A Potential Challenge for 68Ga-DOTATATE, the Clinical Gold Standard for Somatostatin Receptor Imaging with PET.

UNLABELLED: Radiolabeled peptides for tumor imaging with PET that can be produced with kits are currently in the spotlight of radiopharmacy and nuclear medicine. The diagnosis of neuroendocrine tumors in particular has been a prime example for the usefulness of peptides labeled with a variety of different radionuclides. Among those, (68)Ga and (18)F stand out because of the ease of radionuclide introduction (e.g., (68)Ga isotope) or optimal nuclide properties for PET imaging (slightly favoring the (18)F isotope). The in vivo properties of good manufacturing practice-compliant, newly developed kitlike-producible (18)F-SiFA- and (18)F-SiFAlin- (SiFA = silicon-fluoride acceptor) modified TATE derivatives were compared with the current clinical gold standard (68)Ga-DOTATATE for high-quality imaging of somatostatin receptor-bearing tumors. METHODS: SiFA- and SiFAlin-derivatized somatostatin analogs were synthesized and radiolabeled using cartridge-based dried (18)F and purified via a C18 cartridge (radiochemical yield 49.8% ± 5.9% within 20-25 min) without high-performance liquid chromatography purification. Tracer lipophilicity and stability in human serum were tested in vitro. Competitive receptor binding affinity studies were performed using AR42J cells. The most promising tracers were evaluated in vivo in an AR42J xenograft mouse model by ex vivo biodistribution and in vivo PET/CT imaging studies for evaluation of their pharmacokinetic profiles, and the results were compared with those of the current clinical gold standard (68)Ga-DOTATATE. RESULTS: Synthetically easily accessible (18)F-labeled silicon-fluoride acceptor-modified somatostatin analogs were developed. They exhibited high binding affinities to somatostatin receptor-positive tumor cells (1.88-14.82 nM). The most potent compound demonstrated comparable pharmacokinetics and an even slightly higher absolute tumor accumulation level in ex vivo biodistribution studies as well as higher tumor standardized uptake values in PET/CT imaging than (68)Ga-DOTATATE in vivo. The radioactivity uptake in nontumor tissue was higher than for (68)Ga-DOTATATE. CONCLUSION: The introduction of the novel SiFA building block SiFAlin and of hydrophilic auxiliaries enables a favorable in vivo biodistribution profile of the modified TATE peptides, resulting in high tumor-to-background ratios although lower than those observed with (68)Ga-DOTATATE. As further advantage, the SiFA methodology enables a kitlike labeling procedure for (18)F-labeled peptides advantageous for routine clinical application.