The prognostic value of visual and automatic coronary calcium scoring from low-dose computed tomography-[15O]-water positron emission tomography.

AIMS: The study aimed, firstly, to validate automatically and visually scored coronary artery calcium (CAC) on low-dose computed tomography (CT) (LDCT) scans with a dedicated calcium scoring CT (CSCT) scan and, secondly, to assess the added value of CAC scored from LDCT scans acquired during [15O]-water-positron emission tomography (PET) myocardial perfusion imaging (MPI) on prediction of major adverse cardiac events (MACE). METHODS AND RESULTS: Five hundred seventy-two consecutive patients with suspected coronary artery disease, who underwent [15O]-water-PET MPI with LDCT and a dedicated CSCT scan were included. In the reference CSCT scans, manual CAC scoring was performed, while LDCT scans were scored visually and automatically using deep learning approach. Subsequently, based on CAC score results from CSCT and LDCT scans, each patient's scan was assigned to one out of five cardiovascular risk groups (0, 1-100, 101-400, 401-1000, >1000), and the agreement in risk group classification between CSCT and LDCT scans was investigated. MACE was defined as a composite of all-cause death, non-fatal myocardial infarction, coronary revascularization, and unstable angina. The agreement in risk group classification between reference CSCT manual scoring and visual/automatic LDCT scoring from LDCT was 0.66 [95% confidence interval (CI): 0.62-0.70] and 0.58 (95% CI: 0.53-0.62), respectively. Based on visual and automatic CAC scoring from LDCT scans, patients with CAC > 100 and CAC > 400, respectively, were at increased risk of MACE, independently of ischaemic information from the [15O]-water-PET scan. CONCLUSION: There is a moderate agreement in risk classification between visual and automatic CAC scoring from LDCT and reference CSCT scans. Visual and automatic CAC scoring from LDCT scans improve identification of patients at higher risk of MACE.

Halved contrast medium dose coronary dual-layer CT-angiography - phantom study of tube current and patient characteristics.

Virtual mono-energetic images (VMI) using dual-layer computed tomography (DLCT) enable substantial contrast medium (CM) reductions. However, the combined impact of patient size, tube voltage, and heart rate (HR) on VMI of coronary CT angiography (CCTA) remains unknown. This phantom study aimed to assess VMI levels achieving comparable contrast-to-noise ratio (CNR) in CCTA at 50% CM dose across varying tube voltages, patient sizes, and HR, compared to the reference protocol (100% CM dose, conventional at 120 kVp). A 5 mm artificial coronary artery with 100% (400 HU) and 50% (200 HU) iodine CM-dose was positioned centrally in an anthropomorphic thorax phantom. Horizontal coronary movement was matched to HR (at 0, < 60, 60-75, > 75 bpm), with varying patient sizes simulated using phantom extension rings. Raw data was acquired using a clinical CCTA protocol at 120 and 140 kVp (five repetitions). VMI images (40-70 keV, 5 keV steps) were then reconstructed; non-overlapping 95% CNR confidence intervals indicated significant differences from the reference. Higher CM-dose, reduced VMI, slower HR, higher tube voltage, and smaller patient sizes demonstrated a trend of higher CNR. Regardless of HR, patient size, and tube voltage, no significant CNR differences were found compared to the reference, with 100% CM dose at 60 keV, or 50% CM dose at 40 keV. DLCT reconstructions at 40 keV from 120 to 140 kVp acquisitions facilitate 50% CM dose reduction for various patient sizes and HR with equivalent CNR to conventional CCTA at 100% CM dose, although clinical validation is needed.

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.

Systematic assessment of coronary calcium detectability and quantification on four generations of CT reconstruction techniques: a patient and phantom study.

In computed tomography, coronary artery calcium (CAC) scores are influenced by image reconstruction. The effect of a newly introduced deep learning-based reconstruction (DLR) on CAC scoring in relation to other algorithms is unknown. The aim of this study was to evaluate the effect of four generations of image reconstruction techniques (filtered back projection (FBP), hybrid iterative reconstruction (HIR), model-based iterative reconstruction (MBIR), and DLR) on CAC detectability, quantification, and risk classification. First, CAC detectability was assessed with a dedicated static phantom containing 100 small calcifications varying in size and density. Second, CAC quantification was assessed with a dynamic coronary phantom with velocities equivalent to heart rates of 60-75 bpm. Both phantoms were scanned and reconstructed with four techniques. Last, scans of fifty patients were included and the Agatston calcium score was calculated for all four reconstruction techniques. FBP was used as a reference. In the phantom studies, all reconstruction techniques resulted in less detected small calcifications, up to 22%. No clinically relevant quantification changes occurred with different reconstruction techniques (less than 10%). In the patient study, the cardiovascular risk classification resulted, for all reconstruction techniques, in excellent agreement with the reference (κ = 0.96-0.97). However, MBIR resulted in significantly higher Agatston scores (61 (5.5-435.0) vs. 81.5 (9.25-435.0); p < 0.001) and 6% reclassification rate. In conclusion, HIR and DLR reconstructed scans resulted in similar Agatston scores with excellent agreement and low-risk reclassification rate compared with routine reconstructed scans (FBP). However, caution should be taken with low Agatston scores, as based on phantom study, detectability of small calcifications varies with the used reconstruction algorithm, especially with MBIR and DLR.

Automated cardiovascular risk categorization through AI-driven coronary calcium quantification in cardiac PET acquired attenuation correction CT.

BACKGROUND: We present an automatic method for coronary artery calcium (CAC) quantification and cardiovascular risk categorization in CT attenuation correction (CTAC) scans acquired at rest and stress during cardiac PET/CT. The method segments CAC according to visual assessment rather than the commonly used CT-number threshold. METHODS: The method decomposes an image containing CAC into a synthetic image without CAC and an image showing only CAC. Extensive evaluation was performed in a set of 98 patients, each having rest and stress CTAC scans and a dedicated calcium scoring CT (CSCT). Standard manual calcium scoring in CSCT provided the reference standard. RESULTS: The interscan reproducibility of CAC quantification computed as average absolute relative differences between CTAC and CSCT scan pairs was 75% and 85% at rest and stress using the automatic method compared to 121% and 114% using clinical calcium scoring. Agreement between automatic risk assessment in CTAC and clinical risk categorization in CSCT resulted in linearly weighted kappa of 0.65 compared to 0.40 between CTAC and CSCT using clinically used calcium scoring. CONCLUSION: The increased interscan reproducibility achieved by our method may allow routine cardiovascular risk assessment in CTAC, potentially relieving the need for dedicated CSCT.

The multitarget fecal immunochemical test versus the fecal immunochemical test for programmatic colorectal cancer screening: a cross-sectional intervention study with paired design.

BACKGROUND: Many screening programs for colorectal cancer (CRC) use the fecal immunochemical test (FIT) to triage individuals for colonoscopy. Although these programs reduce CRC incidence and CRC-related mortality, the detection of advanced precursor lesions (advanced adenomas and advanced serrated polyps) by FIT could be improved. As an alternative for FIT, the antibody-based multitargetFIT (mtFIT) has been proposed. The mtFIT measures three protein markers: hemoglobin, calprotectin, and serpin family F member 2. In a retrospective diagnostic accuracy study in a large colonoscopy-controlled series (n = 1284), mtFIT showed increased sensitivity for advanced neoplasia (AN), at equal specificity, compared to FIT (42.9% versus 37.3%; p = 0.025). This increase was mainly due to a higher sensitivity of mtFIT for advanced adenomas (37.8% versus 28.1% for FIT; p = 0.006). The present mtFIT study aims to prospectively validate these findings in the context of the Dutch national CRC screening program. METHOD: The mtFIT study is a cross-sectional intervention study with a paired design. Eligible subjects for the Dutch FIT-based national CRC screening program are invited to perform mtFIT in addition to FIT. Samples are collected at home, from the same bowel movement, and are shipped to a central laboratory by postal mail. If either one or both tests are positive, participants are referred for colonoscopy. Detailed colonoscopy and pathology data are centrally stored in a national screening database (ScreenIT; Topicus, Deventer, the Netherlands) that is managed by the screening organization, and will be retrieved for this study. We aim to determine the relative sensitivity for AN, comprising of CRC, advanced adenomas and advanced serrated polyps, of mtFIT compared to FIT at an equal positivity rate. Additionally, we will use the Adenoma and Serrated Pathway to Colorectal CAncer model to predict lifetime health effects and costs for programmatic mtFIT- versus FIT-based screening. The target sample size is 13,131 participants. DISCUSSION: The outcome of this study will inform on the comparative clinical utility of mtFIT versus FIT in the Dutch national CRC screening program and is an important step forward in the development of a new non-invasive stool test for CRC screening. TRIAL REGISTRATION: Clinicaltrials.gov ; NCT05314309, registered April 6th 2022, first inclusions March 25th 2022 https://clinicaltrials.gov/ct2/results?cond=&term=NCT05314309&cntry=&state=&city=&dist =.

Mammographic breast density and the risk of breast cancer: A systematic review and meta-analysis.

OBJECTIVES: Mammographic density is a well-defined risk factor for breast cancer and having extremely dense breast tissue is associated with a one-to six-fold increased risk of breast cancer. However, it is questioned whether this increased risk estimate is applicable to current breast density classification methods. Therefore, the aim of this study was to further investigate and clarify the association between mammographic density and breast cancer risk based on current literature. METHODS: Medline, Embase and Web of Science were systematically searched for articles published since 2013, that used BI-RADS lexicon 5th edition and incorporated data on digital mammography. Crude and maximally confounder-adjusted data were pooled in odds ratios (ORs) using random-effects models. Heterogeneity regarding breast cancer risks were investigated using I2 statistic, stratified and sensitivity analyses. RESULTS: Nine observational studies were included. Having extremely dense breast tissue (BI-RADS density D) resulted in a 2.11-fold (95% CI 1.84-2.42) increased breast cancer risk compared to having scattered dense breast tissue (BI-RADS density B). Sensitivity analysis showed that when only using data that had adjusted for age and BMI, the breast cancer risk was 1.83-fold (95% CI 1.52-2.21) increased. Both results were statistically significant and homogenous. CONCLUSIONS: Mammographic breast density BI-RADS D is associated with an approximately two-fold increased risk of breast cancer compared to having BI-RADS density B in general population women. This is a novel and lower risk estimate compared to previously reported and might be explained due to the use of digital mammography and BI-RADS lexicon 5th edition.

Irregular screening participation increases advanced stage breast cancer at diagnosis: A population-based study.

OBJECTIVE: To evaluate the effect of irregular screening behaviour on the risk of advanced stage breast cancer at diagnosis in Flanders. METHODS: All women aged 50-69 who were invited to the organized breast cancer screening and diagnosed with breast cancer before age 72 from 2001 to 2018 were included. All prevalent screen and interval cancers within 2 years of a prevalent screen were excluded. Screening behaviour was categorized based on the number of invitations and performed screenings. Four groups were defined: regular, irregular, only-once, and never attenders. Advanced stage cancer was defined as a stage III + breast cancer. The association between screening regularity and breast cancer stage at diagnosis was evaluated in multivariable logistic regression models, taking age of diagnosis and socio-economic status into account. RESULTS: In total 13.5% of the 38,005 breast cancer cases were diagnosed at the advanced stage. Compared to the regular attenders, the risk of advanced stage breast cancer for the irregular attenders, women who participated only-once, and never attenders was significantly higher with ORadjusted:1.17 (95%CI:1.06-1.29) and ORadjusted:2.18 (95%CI:1.94-2.45), and ORadjusted:5.95 (95%CI:5.33-6.65), respectively. CONCLUSIONS: In our study, never attenders were nearly six times more likely to be diagnosed with advanced stage breast cancer than regular attenders, which was much higher than the estimates published thus far. An explanation for this is that the ever screened women is a heterogeneous group regarding the participation profiles which also includes irregular and only-once attenders. The benefit of regular screening should be informed to all women invited for screening.

Determinants of Non-Participation in Population-Based Breast Cancer Screening: A Systematic Review and Meta-Analysis.

Background: Breast cancer (BC) screening can be performed in a screening program (BCSP) or in opportunistic screening. The existing reviews on the determinants of non-participation depend on self-reported data which may be biased. Furthermore, no distinction was made between the probably different determinants of both screening strategies. Objective: To find the determinants of non-participation in BCSP by means of a meta-analysis. Methods: PubMed, Embase, and Web of Science were searched for observational studies which quantified factors associated with non-participation in BCSP in a general population. Studies on opportunistic screening and studies using self-reported data were excluded. A random-effect model was used to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Potential sources of heterogeneity were explored by stratification of the results. Results: Twenty-nine studies with in a total of 20,361,756 women were included. Low income (OR: 1.20, 95% CI: 1.10-1.30), low education (OR: 1.18, 95% CI: 1.05-1.32), living far from an assigned screening unit (OR: 1.15, 95% CI: 1.07-1.24), being immigrant (OR: 2.64, 95% CI: 2.48-2.82), and having a male family doctor (OR: 1.43, 95% CI: 1.20-1.61) was associated with higher non-participation in screening. Reminders sent to non-attenders and estimations of ORs (adjusted or not) partly explained substantial heterogeneity. Conclusion: In this meta-analysis excluding studies on the non-participation in opportunistic screening, or with self-reported data on non-participation, the well-known determinants for non-participation are still significant, but less strong. This analysis only supports the relevance of meta-analysis of studies with registered non-participation in a BCSP. Systematic Review Registration: PROSPERO, CRD42020154016.

Improved coronary calcium detection and quantification with low-dose full field-of-view photon-counting CT: a phantom study.

OBJECTIVE: The aim of the current study was to systematically assess coronary artery calcium (CAC) detection and quantification for spectral photon-counting CT (SPCCT) in comparison to conventional CT and, in addition, to evaluate the possibility of radiation dose reduction. METHODS: Routine clinical CAC CT protocols were used for data acquisition and reconstruction of two CAC containing cylindrical inserts which were positioned within an anthropomorphic thorax phantom. In addition, data was acquired at 50% lower radiation dose by reducing tube current, and slice thickness was decreased. Calcifications were considered detectable when three adjacent voxels exceeded the CAC scoring threshold of 130 Hounsfield units (HU). Quantification of CAC (as volume and mass score) was assessed by comparison with known physical quantities. RESULTS: In comparison with CT, SPCCT detected 33% and 7% more calcifications for the small and large phantoms, respectively. At reduced radiation dose and reduced slice thickness, small phantom CAC detection increased by 108% and 150% for CT and SPCCT, respectively. For the large phantom size, noise levels interfered with CAC detection. Although comparable between CT and SPCCT, routine protocols CAC quantification showed large deviations (up to 134%) from physical CAC volume. At reduced radiation dose and slice thickness, physical volume overestimations decreased to 96% and 72% for CT and SPCCT, respectively. In comparison with volume scores, mass score deviations from physical quantities were smaller. CONCLUSION: CAC detection on SPCCT is superior to CT, and was even preserved at a reduced radiation dose. Furthermore, SPCCT allows for improved physical volume estimation. KEY POINTS: • In comparison with conventional CT, increased coronary artery calcium detection (up to 156%) for spectral photon-counting CT was found, even at 50% radiation dose reduction. • Spectral photon-counting CT can more accurately measure physical volumes than conventional CT, especially at reduced slice thickness and for high-density coronary artery calcium. • For both conventional and spectral photon-counting CT, reduced slice thickness reconstructions result in more accurate physical mass approximation.

Coronary calcium scoring potential of large field-of-view spectral photon-counting CT: a phantom study.

OBJECTIVE: The aim of the current study was, first, to assess the coronary artery calcium (CAC) scoring potential of spectral photon-counting CT (SPCCT) in comparison with computed tomography (CT) for routine clinical protocols. Second, improved CAC detection and quantification at reduced slice thickness were assessed. METHODS: Raw data was acquired and reconstructed with several combinations of reduced slice thickness and increasing strengths of iterative reconstruction (IR) for both CT systems with routine clinical CAC protocols for CT. Two CAC-containing cylindrical inserts, consisting of CAC of different densities and sizes, were placed in an anthropomorphic phantom. A specific CAC was detectable when 3 or more connected voxels exceeded the CAC scoring threshold of 130 Hounsfield units (HU). For all reconstructions, total CAC detectability was compared between both CT systems. Significant differences in CAC quantification (Agatston and volume scores) were assessed with Mann-Whitney U tests. Furthermore, volume scores were compared with the known CAC physical. RESULTS: CAC scores for routine clinical protocols were comparable between SPCCT and CT. SPCCT showed 34% and 4% higher detectability of CAC for the small and large phantom, respectively. At reduced slice thickness, CAC detection increased by 142% and 169% for CT and SPCCT, respectively. In comparison with CT, volume scores from SPCCT were more comparable with the physical volume of the CAC. CONCLUSION: CAC scores using routine clinical protocols are comparable between conventional CT and SPCCT. The increased spatial resolution of SPCCT allows for increased detectability and more accurate CAC volume estimation. KEY POINTS: • Coronary artery calcium scores using routine clinical protocols are comparable between conventional CT and spectral photon-counting CT. • In comparison with conventional CT, increased coronary artery calcium detectability was shown for spectral photon-counting CT due to increased spatial resolution. • Volumes scores were more accurately determined with spectral photon-counting CT.

[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.

Cone beam computed tomography for detecting residual stones in percutaneous nephrolithotomy, a randomized controlled trial (CAPTURE) protocol.

INTRODUCTION: Percutaneous nephrolithotomy (PCNL) is the standard surgical treatment method for large kidney stones. Its aim is to achieve a stone-free status, since any residual fragments (RFs) after PCNL are likely to cause additional morbidity or stone growth. Enhancing intraoperative detectability of RFs could lead to increased stone-free rates and decreased re-intervention rates. Cone beam computed tomography (CBCT) has recently been introduced in urology as a feasible method for intraoperatively imaging RFs. The aim of this trial is to determine the added value of CBCT in percutaneous nephrolithotomy, by measuring differences in stone-related morbidity for patients with procedures in which a CBCT is used versus patients with procedures without the use of CBCT. METHODS: The CAPTURE trial is an investigator-initiated single-center, randomized controlled trial (RCT) in adult patients who have an indication for percutaneous nephrolithotomy. A contemporary percutaneous nephrolithotomy is performed. Once the surgeon is convinced of a stone-free status by means of fluoroscopy and nephroscopy, randomization allocates patients to either the study group in whom an intraoperative CBCT scan is performed or to the control group in whom no intraoperative CBCT scan is performed. The main endpoint is the stone-free status as assessed four weeks postoperatively by low-dose non-contrast abdominal CT, as a standard follow-up procedure. Secondary endpoints include the number of PCNL procedures required and the number of stone-related events (SREs) registered. The total study population will consist of 320 patients that undergo PCNL and are eligible for randomization for an intraoperative CBCT scan. DISCUSSION: We deem a randomized controlled trial to be the most effective and reliable method to assess the efficacy of CBCT in PCNL. Though some bias may occur due to the impossibility of blinding the urologist at randomization, we estimate that the pragmatic nature of the study, standardized circumstances, and follow-up methods with pre-defined outcome measures will result in a high level of evidence. TRIAL REGISTRATION: Netherlands Trial Register (NTR) NL8168 , ABR NL70728.042.19. Registered on 15 October 2019. Prospectively registered.

Coverage determinants of breast cancer screening in Flanders: an evaluation of the past decade.

BACKGROUND: Breast cancer (BC) is the most common cancer in women in the developed world. In order to find developing cancers in an early stage, BC screening is commonly used. In Flanders, screening is performed in and outside an organized breast cancer screening program (BCSP). However, the determinants of BC screening coverage for both screening strategies are yet unknown. OBJECTIVE: To assess the determinants of BC screening coverage in Flanders. METHODS: Reimbursement data were used to attribute a screening status to each woman in the target population for the years 2008-2016. Yearly coverage data were categorized as screening inside or outside BCSP or no screening. Data were clustered by municipality level. A generalized linear equation model was used to assess the determinants of screening type. RESULTS: Over all years and municipalities, the median screening coverage rate inside and outside BCSP was 48.40% (IQR: 41.50-54.40%) and 14.10% (IQR: 9.80-19.80%) respectively. A higher coverage rate outside BSCP was statistically significantly (P < 0.001) associated with more crowded households (OR: 3.797, 95% CI: 3.199-4.508), younger age, higher population densities (OR: 2.528, 95% CI: 2.455-2.606), a lower proportion of unemployed job seekers (OR: 0.641, 95% CI: 0.624-0.658) and lower use of dental care (OR: 0.969, 95% CI: 0.967-0.972). CONCLUSION: Coverage rate of BC screening is not optimal in Flanders. Women with low SES that are characterized by younger age, living in a high population density area, living in crowded households, or having low dental care are less likely to be screened for BC in Flanders. If screened, they are more likely to be screened outside the BCSP.

Performance of four platforms for KRAS mutation detection in plasma cell-free DNA: ddPCR, Idylla, COBAS z480 and BEAMing.

Multiple platforms are commercially available for the detection of circulating cell-free tumour DNA (ctDNA) from liquid biopsies. Since platforms have different input and output variables, deciding what platform to use for a given clinical or research question can be daunting. This study aimed to provide insight in platform selection criteria by comparing four commercial platforms that detect KRAS ctDNA hotspot mutations: Bio-Rad droplet digital PCR (ddPCR), BioCartis Idylla, Roche COBAS z480 and Sysmex BEAMing. Platform sensitivities were determined using plasma samples from metastatic colorectal cancer (mCRC) patients and synthetic reference samples, thereby eliminating variability in amount of plasma analysed and ctDNA isolation methods. The prevalence of KRAS nucleotide alterations was set against platform-specific breadth of target. Platform comparisons revealed that ddPCR and BEAMing detect more KRAS mutations amongst mCRC patients than Idylla and COBAS z480. Maximum sample throughput was highest for ddPCR and COBAS z480. Total annual costs were highest for BEAMing and lowest for Idylla and ddPCR. In conclusion, when selecting a platform for detection of ctDNA hotspot mutations the desired test sensitivity, breadth of target, maximum sample throughput, and total annual costs are critical factors that should be taken into consideration. Based on the results of this study, laboratories will be able to select the optimal platform for their needs.

Influence of iterative reconstruction on coronary calcium scores at multiple heart rates: a multivendor phantom study on state-of-the-art CT systems.

The objective of this study was to evaluate the influence of iterative reconstruction on coronary calcium scores (CCS) at different heart rates for four state-of-the-art CT systems. Within an anthropomorphic chest phantom, artificial coronary arteries were translated in a water-filled compartment. The arteries contained three different calcifications with low (38 mg), medium (80 mg) and high (157 mg) mass. Linear velocities were applied, corresponding to heart rates of 0, < 60, 60-75 and > 75 bpm. Data were acquired on four state-of-the-art CT systems (CT1-CT4) with routinely used CCS protocols. Filtered back projection (FBP) and three increasing levels of iterative reconstruction (L1-L3) were used for reconstruction. CCS were quantified as Agatston score and mass score. An iterative reconstruction susceptibility (IRS) index was used to assess susceptibility of Agatston score (IRSAS) and mass score (IRSMS) to iterative reconstruction. IRS values were compared between CT systems and between calcification masses. For each heart rate, differences in CCS of iterative reconstructed images were evaluated with CCS of FBP images as reference, and indicated as small (< 5%), medium (5-10%) or large (> 10%). Statistical analysis was performed with repeated measures ANOVA tests. While subtle differences were found for Agatston scores of low mass calcification, medium and high mass calcifications showed increased CCS up to 77% with increasing heart rates. IRSAS of CT1-T4 were 17, 41, 130 and 22% higher than IRSMS. Not only were IRS significantly different between all CT systems, but also between calcification masses. Up to a fourfold increase in IRS was found for the low mass calcification in comparison with the high mass calcification. With increasing iterative reconstruction strength, maximum decreases of 21 and 13% for Agatston and mass score were found. In total, 21 large differences between Agatston scores from FBP and iterative reconstruction were found, while only five large differences were found between FBP and iterative reconstruction mass scores. Iterative reconstruction results in reduced CCS. The effect of iterative reconstruction on CCS is more prominent with low-density calcifications, high heart rates and increasing iterative reconstruction strength.

Influence of heart rate on coronary calcium scores: a multi-manufacturer phantom study.

To evaluate the influence of heart rate on coronary calcium scores (CCS) using a dynamic phantom on four high-end computed tomography (CT) systems from different manufacturers. Artificial coronary arteries were moved in an anthropomorphic chest phantom at linear velocities, corresponding to < 60, 60-75 and > 75 beats per minute (bpm). Data was acquired with routinely used clinical protocols for CCS on four high-end CT systems (CT1-CT4). CCS, quantified as Agatston and mass scores were compared to reference scores at < 60 bpm. Influence of heart rate was assessed for each system with the cardiac motion susceptibility (CMS) Index. At increased heart rates (> 75 bpm), Agatston scores of the low mass calcification were similar to the reference score, while Agatston scores of the medium and high mass calcification increased significantly up to 50% for all CT systems. Threefold CMS increases at > 75 bpm in comparison with < 60 bpm were shown. For medium and high mass calcifications, significant differences in CMS between CT systems were found. Heart rate substantially influences CCS for high-end CT systems of four major manufacturers, but CT systems differ in motion susceptibility. Follow-up CCS CT scans should be acquired on the same CT system and protocol, and preferably with comparable heart rates.

Influence of dose reduction and iterative reconstruction on CT calcium scores: a multi-manufacturer dynamic phantom study.

To evaluate the influence of dose reduction in combination with iterative reconstruction (IR) on coronary calcium scores (CCS) in a dynamic phantom on state-of-the-art CT systems from different manufacturers. Calcified inserts in an anthropomorphic chest phantom were translated at 20 mm/s corresponding to heart rates between 60 and 75 bpm. The inserts were scanned five times with routinely used CCS protocols at reference dose and 40 and 80% dose reduction on four high-end CT systems. Filtered back projection (FBP) and increasing levels of IR were applied. Noise levels were determined. CCS, quantified as Agatston and mass scores, were compared to physical mass and scores at FBP reference dose. For the reference dose in combination with FBP, noise level variation between CT systems was less than 18%. Decreasing dose almost always resulted in increased CCS, while at increased levels of IR, CCS decreased again. The influence of IR on CCS was smaller than the influence of dose reduction. At reference dose, physical mass was underestimated 3-30%. All CT systems showed similar CCS at 40% dose reduction in combinations with specific reconstructions. For some CT systems CCS was not affected at 80% dose reduction, in combination with IR. This multivendor study showed that radiation dose reductions of 40% did not influence CCS in a dynamic phantom using state-of-the-art CT systems in combination with specific reconstruction settings. Dose reduction resulted in increased noise and consequently increased CCS, whereas increased IR resulted in decreased CCS.

Feasibility of measuring renal blood flow by phase-contrast magnetic resonance imaging in patients with autosomal dominant polycystic kidney disease.

OBJECTIVES: Renal blood flow (RBF) has been shown to predict disease progression in autosomal dominant polycystic kidney disease (ADPKD). We investigated the feasibility and accuracy of phase-contrast RBF by MRI (RBFMRI) in ADPKD patients with a wide range of estimated glomerular filtration rate (eGFR) values. METHODS: First, we validated RBFMRI measurement using phantoms simulating renal artery hemodynamics. Thereafter, we investigated in a test-set of 21 patients intra- and inter-observer coefficient of variation of RBFMRI. After validation, we measured RBFMRI in a cohort of 91 patients and compared the variability explained by characteristics indicative for disease severity for RBFMRI and RBF measured by continuous hippuran infusion. RESULTS: The correlation in flow measurement using phantoms by phase-contrast MRI was high and fluid collection was high (CCC=0.969). Technical problems that precluded RBFMRI measurement occurred predominantly in patients with a lower eGFR (34% vs. 16%). In subjects with higher eGFRs, variability in RBF explained by disease characteristics was similar for RBFMRI compared to RBFHip, whereas in subjects with lower eGFRs, this was significantly less for RBFMRI. CONCLUSIONS: Our study shows that RBF can be measured accurately in ADPKD patients by phase-contrast, but this technique may be less feasible in subjects with a lower eGFR. KEY POINTS: Renal blood flow (RBF) can be accurately measured by phase-contrast MRI in ADPKD patients. RBF measured by phase-contrast is associated with ADPKD disease severity. RBF measurement by phase-contrast MRI may be less feasible in patients with an impaired eGFR.

To screen or not to screen for breast cancer? How do modelling studies answer the question?

Breast cancer screening is a topic of hot debate, and currently no general consensus has been reached on starting and ending ages and screening intervals, in part because of a lack of precise estimations of the benefit-harm ratio. Simulation models are often applied to account for the expected benefits and harms of regular screening; however, the degree to which the model outcomes are reliable is not clear. In a recent systematic review, we therefore aimed to assess the quality of published simulation models for breast cancer screening of the general population. The models were scored according to a framework for qualitative assessment. We distinguished seven original models that utilized a common model type, modelling approach, and input parameters. The models predicted the benefit of regular screening in terms of mortality reduction; and overall, their estimates compared well to estimates of mortality reduction from randomized controlled trials. However, the models did not report on the expected harms associated with regular screening. We found that current simulation models for population breast cancer screening are prone to many pitfalls; their outcomes bear a high overall risk of bias, mainly because of a lack of systematic evaluation of evidence to calibrate the input parameters and a lack of external validation. Our recommendations concerning future modelling are therefore to use systematically evaluated data for the calibration of input parameters, to perform external validation of model outcomes, and to account for both the expected benefits and the expected harms so as to provide a clear balance and cost-effectiveness estimation and to adequately inform decision-makers.