Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Comparison of image quality and spatial resolution between ¹⁸F, ⁶⁸Ga, and ⁶⁴Cu phantom measurements using a digital Biograph Vision PET/CT

Background: PET nuclides can have a considerable influence on the spatial resolution and image quality of PET/CT scans, which can influence diagnostics in oncology, for example. The individual impact of the positron energy of ¹⁸F, ⁶⁸Ga, and ⁶⁴Cu on spatial resolution and image quality was compared for PET/CT scans acquired using a clinical, digital scanner. - Methods: A Jaszczak phantom and a NEMA PET body phantom were filled with ¹⁸F-FDG, ⁶⁸Ga-HCl, or ⁶⁴Cu-HCl, and PET/CT scans were performed on a Siemens Biograph Vision. Acquired images were analyzed regarding spatial resolution and image quality (recovery coefficients (RC), coefficient of variation within the background, contrast recovery coefficient (CRC), contrast–noise ratio (CNR), and relative count error in the lung insert). Data were compared between scans with different nuclides.- Results: We found that image quality was comparable between ¹⁸F-FDG and ⁶⁴Cu-HCl PET/CT measurements featuring similar maximal endpoint energies of the positrons. In comparison, RC, CRC, and CNR were degraded in ⁶⁸Ga-HCl data despite similar count rates. In particular, the two smallest spheres of 10 mm and 13 mm diameter revealed lower RC, CRC, and CNR values. The spatial resolution was similar between ¹⁸F-FDG and ⁶⁴Cu-HCl but up to 18% and 23% worse compared with PET/CT images of the NEMA PET body phantom filled with ⁶⁸Ga-HCl. - Conclusions: The positron energy of the PET nuclide influences the spatial resolution and image quality of a digital PET/CT scan. The image quality and spatial resolution of ⁶⁸Ga-HCl PET/CT images were worse than those of ¹⁸F-FDG or ⁶⁴Cu-HCl despite similar count rates

A method for model-free partial volume correction in oncological PET

BACKGROUND: As is well known, limited spatial resolution leads to partial volume effects (PVE) and consequently to limited signal recovery. Determination of the mean activity concentration of a target structure is thus compromised even at target sizes much larger than the reconstructed spatial resolution. This leads to serious size-dependent underestimates of true signal intensity in hot spot imaging. For quantitative PET in general and in the context of therapy assessment in particular it is, therefore, mandatory to perform an adequate partial volume correction (PVC). The goal of our work was to develop and to validate a model-free PVC algorithm for hot spot imaging. METHODS: The algorithm proceeds in two automated steps. Step 1: estimation of the actual object boundary with a threshold based method and determination of the total activity A measured within the enclosed volume V. Step 2: determination of the activity fraction B, which is measured outside the object due to the partial volume effect (spill-out). The PVE corrected mean value is then given by C(mean) = (A+B)/V. For validation simulated tumours were used which were derived from real patient data (liver metastases of a colorectal carcinoma and head and neck cancer, respectively). The simulated tumours have characteristics (regarding tumour shape, contrast, noise, etc.) which are very similar to those of the underlying patient data, but the boundaries and tracer accumulation are exactly known. The PVE corrected mean values of 37 simulated tumours were determined and compared with the true mean values. RESULTS: For the investigated simulated data the proposed approach yields PVE corrected mean values which agree very well with the true values (mean deviation (± s.d.): (−0.8±2.5)%). CONCLUSIONS: The described method enables accurate quantitative partial volume correction in oncological hot spot imaging

Interobserver variability of image-derived arterial blood SUV in whole-body FDG PET

Abstract Background Today, the standardized uptake value (SUV) is essentially the only means for quantitative evaluation of static [18F-]fluorodeoxyglucose (FDG) positron emission tomography (PET) investigations. However, the SUV approach has several well-known shortcomings which adversely affect the reliability of the SUV as a surrogate of the metabolic rate of glucose consumption. The standard uptake ratio (SUR), i.e., the uptake time-corrected ratio of tumor SUV to image-derived arterial blood SUV, has been shown in the first clinical studies to overcome most of these shortcomings, to decrease test-retest variability, and to increase the prognostic value in comparison to SUV. However, it is unclear, to what extent the SUR approach is vulnerable to observer variability of the additionally required blood SUV (BSUV) determination. The goal of the present work was the investigation of the interobserver variability of image-derived BSUV. Methods FDG PET/CT scans from 83 patients (72 male, 11 female) with non-small cell lung cancer (N = 46) or head and neck cancer (N = 37) were included. BSUV was determined by 8 individuals, each applying a dedicated delineation tool for the BSUV determination in the aorta. Two of the observers applied two further tools. Altogether, five different delineation tools were used. With each used tool, delineation was performed for the whole patient group, resulting in 12 distinct observations per patient. Intersubject variability of BSUV determination was assessed using the fractional deviations for the individual patients from the patient group average and was quantified as standard deviation (SD is ), 95% confidence interval, and range. Interobserver variability of BSUV determination was assessed using the fractional deviations of the individual observers from the observer-average for the considered patient and quantified as standard deviations (SD p , SD d ) or root mean square (RMS), 95% confidence interval, and range in each patient, each observer, and the pooled data respectively. Results Interobserver variability in the pooled data amounts to RMS = 2.8% and is much smaller than the intersubject variability of BSUV (SD is = 16%). Averaged over the whole patient group, deviations of individual observers from the observer average are very small and fall in the range [ − 0.96, 1.05]%. However, interobserver variability partly differs distinctly for different patients, covering a range of [0.7, 7.4]% in the investigated patient group. Conclusion The present investigation demonstrates that the image-based manual determination of BSUV in the aorta is sufficiently reproducible across different observers and delineation tools which is a prerequisite for accurate SUR determination. This finding is in line with the already demonstrated superior prognostic value of SUR in comparison to SUV in the first clinical studies

ORIGINAL RESEARCH Open Access Correction of scan time dependence of standard uptake values in oncological PET

Background: Standard uptake values (SUV) as well as tumor-to-blood standard uptake ratios (SUR) measured with [18F-]fluorodeoxyglucose (FDG) PET are time dependent. This poses a serious problem for reliable quantification since variability of scan start time relative to the time of injection is a persistent issue in clinical oncological Positron emission tomography (PET). In this work, we present a method for scan time correction of, both, SUR and SUV. Methods: Assuming irreversible FDG kinetics, SUR is linearly correlated to Km (the metabolic rate of FDG), where the slope only depends on the shape of the arterial input function (AIF) and on scan time. Considering the approximately invariant shape of the AIF, this slope (the ‘Patlak time’) is an investigation independent function of scan time. This fact can be used to map SUR and SUV values from different investigations to a common time point for quantitative comparison. Additionally, it turns out that modelling the invariant AIF shape by an inverse power law is possible which further simplifies the correction procedure. The procedure was evaluated in 15 fully dynamic investigations of liver metastases from colorectal cancer and 10 dual time point (DTP) measurements. From each dynamic study, three ‘static scans ’ at T = 20, 35, and 55 min post injection (p.i.) were created, where the last scan defined the reference time point to which the uptake values measured in the other two were corrected. The corrected uptake values were then compared to those actually measured at the reference time. For the DTP studies, the first scan (acquired a

PET/MR for therapy response evaluation in malignant lymphoma: initial experience

OBJECT: To evaluate the feasibility of positron emission tomography/magnetic resonance imaging (PET/MR) with (18)fluoro-2-deoxyglucose (FDG) for therapy response evaluation of malignant lymphoma. MATERIALS AND METHODS: Nine patients with malignant lymphoma who underwent FDG-PET/MR before and after chemotherapy were included in this retrospective study. Average time between the two scans was 70 days. The scans were evaluated independently by two nuclear medicine physicians. The Ann Arbor classification was used to describe lymphoma stage. Furthermore, the readers also rated PET image quality using a five point scale. Weighted kappa (κ) was used to calculate interrater agreement. RESULTS: The initial scan showed foci of increased FDG uptake in all patients, with Ann Arbor stage varying between I and IV. In the follow-up examination, all but one patient showed complete response to chemotherapy. PET image quality was rated as very good or excellent for all scans. Interrater agreement was excellent regarding Ann Arbor stage (κ = 0.97) and good regarding image quality (κ = 0.41). CONCLUSION: PET/MR shows promising initial results for therapy response evaluation in lymphoma patients

Effects of systematic partial volume errors on the estimation of gray matter cerebral blood flow with arterial spin labeling MRI

Objective: Partial volume (PV) correction is an important step in arterial spin labeling (ASL) MRI that is used to separate perfusion from structural effects when computing the mean gray matter (GM) perfusion. There are three main methods for performing this correction: (1) GM-threshold, which includes only voxels with GM volume above a preset threshold; (2) GM-weighted, which uses voxel-wise GM contribution combined with thresholding; and (3) PVC, which applies a spatial linear regression algorithm to estimate the flow contribution of each tissue at a given voxel. In all cases, GM volume is obtained using PV maps extracted from the segmentation of the T1-weighted (T1w) image. As such, PV maps contain errors due to the difference in readout type and spatial resolution between ASL and T1w images. Here, we estimated these errors and evaluated their effect on the performance of each PV correction method in computing GM cerebral blood flow (CBF). Materials and methods: Twenty-two volunteers underwent scanning using 2D echo planar imaging (EPI) and 3D spiral ASL. For each PV correction method, GM CBF was computed using PV maps simulated to contain estimated errors due to spatial resolution mismatch and geometric distortions which are caused by the mismatch in readout between ASL and T1w images. Results were analyzed to assess the effect of each error on the estimation of GM CBF from ASL data. Results: Geometric distortion had the largest effect on the 2D EPI data, whereas the 3D spiral was most affected by the resolution mismatch. The PVC method outperformed the GM-threshold even in the presence of combined errors from resolution mismatch and geometric distortions. The quantitative advantage of PVC was 16% without and 10% with the combined errors for both 2D and 3D ASL. Consistent with theoretical expectations, for error-free PV maps, the PVC method extracted the true GM CBF. In contrast, GM-weighted overestimated GM CBF by 5%, while GM-threshold underestimated it by 16%. The presence of PV map errors decreased the calculated GM CBF for all methods. Conclusion: The quality of PV maps presents no argument for the preferential use of the GM-threshold method over PVC in the clinical application of ASL

A convolutional neural network for fully automated blood SUV determination to facilitate SUR computation in oncological FDG-PET

Purpose!#!The standardized uptake value (SUV) is widely used for quantitative evaluation in oncological FDG-PET but has well-known shortcomings as a measure of the tumor's glucose consumption. The standard uptake ratio (SUR) of tumor SUV and arterial blood SUV (BSUV) possesses an increased prognostic value but requires image-based BSUV determination, typically in the aortic lumen. However, accurate manual ROI delineation requires care and imposes an additional workload, which makes the SUR approach less attractive for clinical routine. The goal of the present work was the development of a fully automated method for BSUV determination in whole-body PET/CT.!##!Methods!#!Automatic delineation of the aortic lumen was performed with a convolutional neural network (CNN), using the U-Net architecture. A total of 946 FDG PET/CT scans from several sites were used for network training (N = 366) and testing (N = 580). For all scans, the aortic lumen was manually delineated, avoiding areas affected by motion-induced attenuation artifacts or potential spillover from adjacent FDG-avid regions. Performance of the network was assessed using the fractional deviations of automatically and manually derived BSUVs in the test data.!##!Results!#!The trained U-Net yields BSUVs in close agreement with those obtained from manual delineation. Comparison of manually and automatically derived BSUVs shows excellent concordance: the mean relative BSUV difference was (mean ± SD) = (- 0.5 ± 2.2)% with a 95% confidence interval of [- 5.1,3.8]% and a total range of [- 10.0, 12.0]%. For four test cases, the derived ROIs were unusable (< 1 ml).!##!Conclusion!#!CNNs are capable of performing robust automatic image-based BSUV determination. Integrating automatic BSUV derivation into PET data processing workflows will significantly facilitate SUR computation without increasing the workload in the clinical setting