Toward Reliable Uptake Metrics in Large Vessel Vasculitis Studies

The aim of this study is to investigate the influence of sex, age, fat mass, fasting blood glucose level (FBGL), and estimated glomerular filtration rate (eGFR) on blood pool activity in patients with large vessel vasculitis (LVV). Blood pool activity was measured in the superior caval vein using mean, maximum, and peak standardized uptake values corrected for body weight (SUVs) and lean body mass (SULs) in 41 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scans of LVV patients. Sex influence on the blood pool activity was assessed with t-tests, while linear correlation analyses were used for age, fat mass, FBGL, and eGFR. Significantly higher SUVs were found in women compared with men, whereas SULs were similar between sexes. In addition, higher fat mass was associated with increased SUVs (r = 0.56 to 0.65; all p p > 0.05). Lower eGFR was associated with a higher FDG blood pool activity for all uptake values. In FDG-PET/CT studies with LVV patients, we recommend using SUL over SUV, while caution is advised in interpreting SUV and SUL measures when patients have impaired kidney function

[18F]FDG and [18F]NaF as PET markers of systemic atherosclerosis progression:A longitudinal descriptive imaging study in patients with type 2 diabetes mellitus

BACKGROUND: While [18F]-fluordeoxyglucose ([18F]FDG) uptake is associated with arterial inflammation, [18F]-sodium fluoride ([18F]NaF) is a marker for arterial micro-calcification. We aimed to investigate the prospective correlation between both PET markers over time and whether they are prospectively ([18F]FDG) and retrospectively ([18F]NaF) related to progression of systemic arterial disease in a longitudinal study in patients with type 2 diabetes mellitus (T2DM). METHODS: Baseline [18F]FDG PET/Low Dose (LD) Computed Tomography (CT) scans of ten patients with early T2DM without cardiovascular history (70% men, median age 63 years) were compared with five-year follow-up [18F]NaF/LDCT scans. Systemic activity was expressed as mean target-to-background ratio (meanTBR) by dividing the maximal standardized uptake value (SUVmax) of ten arteries by SUVmean of the caval vein. CT-assessed macro-calcifications were scored visually and expressed as calcified plaque (CP) score. Arterial stiffness was assessed with carotid-femoral pulse wave velocity (PWV). Five-year changes were expressed absolutely with delta (Δ) and relatively with %change. RESULTS: Baseline meanTBR[18F]FDG was strongly correlated with five-year follow-up meanTBR[18F]NaF (r = 0.709, P = .022). meanTBR[18F]NaF correlated positively with ΔCPscore, CPscore at baseline, and follow-up (r = 0.845, P = .002 and r = 0.855, P = .002, respectively), but not with %change in CPscore and PWV. CONCLUSION: This proof-of-concept study demonstrated that systemic arterial inflammation is an important pathogenetic factor in systemic arterial micro-calcification development

Severely increased albuminuria in patients with type 2 diabetes mellitus is associated with increased subclinical atherosclerosis in femoral arteries with Na [¹⁸F]F activity as a proxy:The DETERMINE study

Background and aims: Sodium [18F]fluoride (Na [18F]F) positron emission tomography imaging allows detailed visualization of early arterial micro-calcifications. This study aims to investigate atherosclerosis manifested by micro-calcification, macro-calcification, and aortic stiffness in patients with type 2 diabetes mellitus (T2DM) with and without albuminuria and severely decreased kidney function.Methods: A cohort was stratified in four groups (N = 10 per group), based on KDIGO categories (G1-5 A1-3). G1-2A1 non-diabetic controls (median [IQR] estimated glomerular filtration rate (eGFR) in mL/min/1.73 m2 91 [81–104]), G1-2A1 with T2DM (eGFR 87 [84–93], and albumin-creatinin-ratio (ACR) in mg/mmol 0.35 [0.25–0.75]), G1-2A3 with T2DM (eGFR 85 [60–103], and ACR 74 [62–122], and G4A3 with T2DM (eGFR 19 [13-27] and ACR 131 [59–304]). Results: Na [18F]F femoral artery grading score differed significantly in the groups with the highest Na [18F]F activity in A3 groups with T2DM (G1-2A3 with T2DM 228 [100–446] and G4A3 with T2DM 198 [113–578]) from the lowest groups of the G1-2A1 with T2DM (33 [0–93]) and in G1-2A1 non-diabetic controls (75 [0–200], p = 0.001). Aortic Na [18F]F activity and femoral artery computed tomography (CT)-assessed macro-calcification was increased in G4A3 with T2DM compared with G1-2A1 with T2DM (47.5 [33.8–73.8] vs. 17.5 [8.8–27.5] (p = 0.006) and 291 [170–511] vs. 12.2 [1.41–44.3] mg (p = 0.032), respectively). Carotid-femoral pulse wave velocity (PWV)-assessed aortic stiffness was significantly higher in both A3 groups with T2DM compared with G1-2A1 with T2DM (11.15 and 12.35 vs. 8.86 m/s, respectively (p = 0.009)). Conclusions: This study indicates that the presence of severely increased albuminuria in patients with T2DM is cross-sectionally associated with subclinical arterial disease in terms of micro-calcification and aortic stiffness. Additional decrease in kidney function was associated with advanced macro-calcifications.</p

Severely increased albuminuria in patients with type 2 diabetes mellitus is associated with increased subclinical atherosclerosis in femoral arteries with Na [¹⁸F]F activity as a proxy - The DETERMINE study

Background and aims: Sodium [18F]fluoride (Na [18F]F) positron emission tomography imaging allows detailed visualization of early arterial micro-calcifications. This study aims to investigate atherosclerosis manifested by micro-calcification, macro-calcification, and aortic stiffness in patients with type 2 diabetes mellitus (T2DM) with and without albuminuria and severely decreased kidney function. Methods: A cohort was stratified in four groups (N = 10 per group), based on KDIGO categories (G1-5 A1-3). G1-2A1 non-diabetic controls (median [IQR] estimated glomerular filtration rate (eGFR) in mL/min/1.73 m2 91 [81–104]), G1-2A1 with T2DM (eGFR 87 [84–93], and albumin-creatinin-ratio (ACR) in mg/mmol 0.35 [0.25–0.75]), G1-2A3 with T2DM (eGFR 85 [60–103], and ACR 74 [62–122], and G4A3 with T2DM (eGFR 19 [13-27] and ACR 131 [59–304]). Results: Na [18F]F femoral artery grading score differed significantly in the groups with the highest Na [18F]F activity in A3 groups with T2DM (G1-2A3 with T2DM 228 [100–446] and G4A3 with T2DM 198 [113–578]) from the lowest groups of the G1-2A1 with T2DM (33 [0–93]) and in G1-2A1 non-diabetic controls (75 [0–200], p = 0.001). Aortic Na [18F]F activity and femoral artery computed tomography (CT)-assessed macro-calcification was increased in G4A3 with T2DM compared with G1-2A1 with T2DM (47.5 [33.8–73.8] vs. 17.5 [8.8–27.5] (p = 0.006) and 291 [170–511] vs. 12.2 [1.41–44.3] mg (p = 0.032), respectively). Carotid-femoral pulse wave velocity (PWV)-assessed aortic stiffness was significantly higher in both A3 groups with T2DM compared with G1-2A1 with T2DM (11.15 and 12.35 vs. 8.86 m/s, respectively (p = 0.009)). Conclusions: This study indicates that the presence of severely increased albuminuria in patients with T2DM is cross-sectionally associated with subclinical arterial disease in terms of micro-calcification and aortic stiffness. Additional decrease in kidney function was associated with advanced macro-calcifications.</p

Performance Evaluation of a Semi-automated Method for [F-18]FDG Uptake in Abdominal Visceral Adipose Tissue

PurposeSeverity of abdominal obesity and possibly levels of metabolic activity of abdominal visceral adipose tissue (VAT) are associated with an increased risk for cardiovascular disease (CVD). In this context, the purpose of the current study was to evaluate the reproducibility and repeatability of a semi-automated method for assessment of the metabolic activity of VAT using 2-deoxy-2-[F-18]fluoro-D-glucose ([F-18]FDG) positron emission tomography (PET)/x-ray computed tomography (CT).ProceduresTen patients with lung cancer who underwent two baseline whole-body [F-18]FDG PET/low-dose (LD) CT scans within 1week were included. Abdominal VAT was automatically segmented using CT between levels L1-L5. The initial CT-based segmentation was further optimized using PET data with a standardized uptake value (SUV) threshold approach (range 1.0-2.5) and morphological erosion (range 0-5 pixels). The [F-18]FDG uptake in SUV that was measured by the automated method was compared with manual analysis. The reproducibility and repeatability were quantified using intraclass correlation coefficients (ICCs).ResultsThe metabolic assessment of VAT on [F-18]FDG PET/LDCT scans expressed as SUVmean, using an automated method showed high inter and intra observer (all ICCs >0.99) and overall repeatability (ICC=0.98). The manual method showed reproducible inter observer (all ICCs >0.92), but less intra observer (ICC=0.57) and less overall repeatability (ICC=0.78) compared with the automated method.ConclusionsOur proposed semi-automated method provided reproducible and repeatable quantitative analysis of [F-18]FDG uptake in VAT. We expect this method to aid future research regarding the role of VAT in development of CVD.</div

Performance Evaluation of a Semi-automated Method for [F-18]FDG Uptake in Abdominal Visceral Adipose Tissue

PURPOSE: Severity of abdominal obesity and possibly levels of metabolic activity of abdominal visceral adipose tissue (VAT) are associated with an increased risk for cardiovascular disease (CVD). In this context, the purpose of the current study was to evaluate the reproducibility and repeatability of a semi-automated method for assessment of the metabolic activity of VAT using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET)/x-ray computed tomography (CT). PROCEDURES: Ten patients with lung cancer who underwent two baseline whole-body [18F]FDG PET/low-dose (LD) CT scans within 1 week were included. Abdominal VAT was automatically segmented using CT between levels L1-L5. The initial CT-based segmentation was further optimized using PET data with a standardized uptake value (SUV) threshold approach (range 1.0-2.5) and morphological erosion (range 0-5 pixels). The [18F]FDG uptake in SUV that was measured by the automated method was compared with manual analysis. The reproducibility and repeatability were quantified using intraclass correlation coefficients (ICCs). RESULTS: The metabolic assessment of VAT on [18F]FDG PET/LDCT scans expressed as SUVmean, using an automated method showed high inter and intra observer (all ICCs > 0.99) and overall repeatability (ICC = 0.98). The manual method showed reproducible inter observer (all ICCs > 0.92), but less intra observer (ICC = 0.57) and less overall repeatability (ICC = 0.78) compared with the automated method. CONCLUSIONS: Our proposed semi-automated method provided reproducible and repeatable quantitative analysis of [18F]FDG uptake in VAT. We expect this method to aid future research regarding the role of VAT in development of CVD

Automated multiclass segmentation, quantification, and visualization of the diseased aorta on hybrid PET/CT–SEQUOIA

Background Cardiovascular disease is the most common cause of death worldwide, including infection and inflammation related conditions. Multiple studies have demonstrated potential advantages of hybrid positron emission tomography combined with computed tomography (PET/CT) as an adjunct to current clinical inflammatory and infectious biochemical markers. To quantitatively analyze vascular diseases at PET/CT, robust segmentation of the aorta is necessary. However, manual segmentation is extremely time-consuming and labor-intensive. Purpose To investigate the feasibility and accuracy of an automated tool to segment and quantify multiple parts of the diseased aorta on unenhanced low-dose computed tomography (LDCT) as an anatomical reference for PET-assessed vascular disease. Methods A software pipeline was developed including automated segmentation using a 3D U-Net, calcium scoring, PET uptake quantification, background measurement, radiomics feature extraction, and 2D surface visualization of vessel wall calcium and tracer uptake distribution. To train the 3D U-Net, 352 non-contrast LDCTs from (2-[18F]FDG and Na[18F]F) PET/CTs performed in patients with various vascular pathologies with manual segmentation of the ascending aorta, aortic arch, descending aorta, and abdominal aorta were used. The last 22 consecutive scans were used as a hold-out internal test set. The remaining dataset was randomly split into training (n = 264; 80%) and validation (n = 66; 20%) sets. Further evaluation was performed on an external test set of 49 PET/CTs. The dice similarity coefficient (DSC) and Hausdorff distance (HD) were used to assess segmentation performance. Automatically obtained calcium scores and uptake values were compared with manual scoring obtained using clinical softwares (syngo.via and Affinity Viewer) in six patient images. intraclass correlation coefficients (ICC) were calculated to validate calcium and uptake values. Results Fully automated segmentation of the aorta using a 3D U-Net was feasible in LDCT obtained from PET/CT scans. The external test set yielded a DSC of 0.867 ± 0.030 and HD of 1.0 [0.6–1.4] mm, similar to an open-source model with a DSC of 0.864 ± 0.023 and HD of 1.4 [1.0–1.8] mm. Quantification of calcium and uptake values were in excellent agreement with clinical software (ICC: 1.00 [1.00–1.00] and 0.99 [0.93–1.00] for calcium and uptake values, respectively). Conclusions We present an automated pipeline to segment the ascending aorta, aortic arch, descending aorta, and abdominal aorta on LDCT from PET/CT and to accurately provide uptake values, calcium scores, background measurement, radiomics features, and a 2D visualization. We call this algorithm SEQUOIA (SEgmentation, QUantification, and visualizatiOn of the dIseased Aorta) and is available at https://github.com/UMCG-CVI/SEQUOIA. This model could augment the utility of aortic evaluation at PET/CT studies tremendously, irrespective of the tracer, and potentially provide fast and reliable quantification of cardiovascular diseases in clinical practice, both for primary diagnosis and disease monitoring

Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial

Background The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak.Methods This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged >= 18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1-9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020-001236-10).Findings Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56-73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0.95 [95% CI 0.76-1.20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0.51 [0.27-0.95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0.52 (95% CI 0.26-1.05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1.07 (0.63-1.80; p=0.81). The median duration of invasive mechanical ventilation was 7 days (IQR 3-13) in the imatinib group compared with 12 days (6-20) in the placebo group (p=0.0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events.Interpretation The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings. Copyright (C) 2021 Elsevier Ltd. All rights reserved.Pathogenesis and treatment of chronic pulmonary disease