Supplemental MRI Screening for Women with Extremely Dense Breast Tissue.

BACKGROUND: Extremely dense breast tissue is a risk factor for breast cancer and limits the detection of cancer with mammography. Data are needed on the use of supplemental magnetic resonance imaging (MRI) to improve early detection and reduce interval breast cancers in such patients. METHODS: In this multicenter, randomized, controlled trial in the Netherlands, we assigned 40,373 women between the ages of 50 and 75 years with extremely dense breast tissue and normal results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The groups were assigned in a 1:4 ratio, with 8061 in the MRI-invitation group and 32,312 in the mammography-only group. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period. RESULTS: The interval-cancer rate was 2.5 per 1000 screenings in the MRI-invitation group and 5.0 per 1000 screenings in the mammography-only group, for a difference of 2.5 per 1000 screenings (95% confidence interval [CI], 1.0 to 3.7; P<0.001). Of the women who were invited to undergo MRI, 59% accepted the invitation. Of the 20 interval cancers that were diagnosed in the MRI-invitation group, 4 were diagnosed in the women who actually underwent MRI (0.8 per 1000 screenings) and 16 in those who did not accept the invitation (4.9 per 1000 screenings). The MRI cancer-detection rate among the women who actually underwent MRI screening was 16.5 per 1000 screenings (95% CI, 13.3 to 20.5). The positive predictive value was 17.4% (95% CI, 14.2 to 21.2) for recall for additional testing and 26.3% (95% CI, 21.7 to 31.6) for biopsy. The false positive rate was 79.8 per 1000 screenings. Among the women who underwent MRI, 0.1% had either an adverse event or a serious adverse event during or immediately after the screening. CONCLUSIONS: The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography resulted in the diagnosis of significantly fewer interval cancers than mammography alone during a 2-year screening period. (Funded by the University Medical Center Utrecht and others; DENSE ClinicalTrials.gov number, NCT01315015.).

Supplemental Breast MRI for Women with Extremely Dense Breasts: Results of the Second Screening Round of the DENSE Trial.

Background In the first (prevalent) supplemental MRI screening round of the Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial, a considerable number of breast cancers were found at the cost of an increased false-positive rate (FPR). In incident screening rounds, a lower cancer detection rate (CDR) is expected due to a smaller pool of prevalent cancers, and a reduced FPR, due to the availability of prior MRI examinations. Purpose To investigate screening performance indicators of the second round (incidence round) of the DENSE trial. Materials and Methods The DENSE trial (ClinicalTrials.gov: NCT01315015) is embedded within the Dutch population-based biennial mammography screening program for women aged 50-75 years. MRI examinations were performed between December 2011 and January 2016. Women were eligible for the second round when they again had a negative screening mammogram 2 years after their first MRI. The recall rate, biopsy rate, CDR, FPR, positive predictive values, and distributions of tumor characteristics were calculated and compared with results of the first round using 95% CIs and χ2 tests. Results A total of 3436 women (median age, 56 years; interquartile range, 48-64 years) underwent a second MRI screening. The CDR was 5.8 per 1000 screening examinations (95% CI: 3.8, 9.0) compared with 16.5 per 1000 screening examinations (95% CI: 13.3, 20.5) in the first round. The FPR was 26.3 per 1000 screening examinations (95% CI: 21.5, 32.3) in the second round versus 79.8 per 1000 screening examinations (95% CI: 72.4, 87.9) in the first round. The positive predictive value for recall was 18% (20 of 110 participants recalled; 95% CI: 12.1, 26.4), and the positive predictive value for biopsy was 24% (20 of 84 participants who underwent biopsy; 95% CI: 16.0, 33.9), both comparable to that of the first round. All tumors in the second round were stage 0-I and node negative. Conclusion The incremental cancer detection rate in the second round was 5.8 per 1000 screening examinations-compared with 16.5 per 1000 screening examinations in the first round. This was accompanied by a strong reduction in the number of false-positive results. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Moy and Gao in this issue.

Histopathological characterization of intimal lesions and arterial wall calcification in the arteries of the leg of elderly cadavers.

INTRODUCTION: Although arteries of the leg have been studied in extensively diseased amputation specimens, little is known about the composition of vascular lesions present in the general population. The aim of this study was to describe the natural development of adaptive intimal thickening, atherosclerotic lesion development and vascular calcification in the leg of a general elderly population. MATERIALS AND METHODS: Two hundred and seventy postmortem samples from the popliteal and posterior tibial arteries of 14 elderly cadavers were studied histologically. RESULTS: Atherosclerotic lesions were more frequently observed in the popliteal (60%) than in the posterior tibial artery (34%; p < .0005). These atherosclerotic plaques were most often nonatheromatous (80% and 83% for popliteal and posterior tibial plaques, respectively). The atheroma's that were present were small (most <25% of plaque area). Atherosclerotic plaque calcification was observed more often in the popliteal (39%) than in the posterior tibial samples (17%; p < .0005). Medial arterial calcification was observed more often in the posterior tibial (62%) than in the popliteal samples (46%; p = .008). Plaque calcification and medial arterial calcification were not associated with lumen stenosis. CONCLUSIONS: In the leg of elderly cadavers, the presence of atherosclerotic plaque and intimal calcification decreases from the proximal popliteal artery to the more distal posterior tibial artery and most atherosclerotic lesions are of the fibrous nonatheromatous type. In contrast, the presence and severity of medial calcification increases from proximal to distal.

Validation of randomized controlled trial-derived models for the prediction of postintervention outcomes in chronic limb-threatening ischemia.

BACKGROUND: Chronic limb-threatening ischemia (CLTI) represents the most severe form of peripheral artery disease and has a large impact on quality of life, morbidity, and mortality. Interventions are aimed at improving tissue perfusion and averting amputation and secondary cardiovascular complications with an optimal risk-benefit ratio. Several prediction models regarding postprocedural outcomes in CLTI patients have been developed on the basis of randomized controlled trials to improve clinical decision-making. We aimed to determine model performance in predicting clinical outcomes in selected CLTI cohorts. METHODS: This study validated the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL), Finland National Vascular registry (FINNVASC), and Prevention of Infrainguinal Vein Graft Failure (PREVENT III) models in data sets from a peripheral artery disease registry study (Athero-Express) and two randomized controlled trials of CLTI in The Netherlands, Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) and Percutaneous Transluminal Angioplasty and Drug-eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia (PADI). Receiver operating characteristic (ROC) curve analysis was used to calculate their predictive capacity. The primary outcome was amputation-free survival (AFS); secondary outcomes were all-cause mortality and amputation at 12 months after intervention. RESULTS: The BASIL and PREVENT III models showed predictive values regarding postintervention mortality in the JUVENTAS cohort with an area under the ROC curve (AUC) of 81% and 70%, respectively. Prediction of AFS was poor to fair (AUC, 0.60-0.71) for all models in each population, with the highest predictive value of 71% for the BASIL model in the JUVENTAS population. The FINNVASC model showed the highest predictive value regarding amputation risk in the PADI population with AUC of 78% at 12 months. CONCLUSIONS: In general, all models performed poor to fair in predicting mortality and amputation. Because the BASIL model performed best in predicting AFS, we propose use of the BASIL model to aid in the clinical decision-making process in CLTI. However, improvements in performance have to be made for any of these models to be of real additional value in clinical practice.

Hippocampal Calcifications: Risk Factors and Association with Cognitive Function.

Purpose To identify risk factors for hippocampal calcifications and to investigate the association between hippocampal calcifications and cognitive function. Materials and Methods For this retrospective study, consecutive patients visiting a memory clinic at a Dutch general hospital between April 2009 and April 2015 were identified. All individuals underwent a standard diagnostic work-up including cognitive tests and brain CT. The following vascular risk factors were assessed: hypertension, diabetes mellitus, hyperlipidemia, and smoking. Cognitive screening consisted of the Cambridge Cognitive Examination, which includes the Mini-Mental State Examination. CT scans were analyzed for the presence and severity (absent, mild, moderate, severe) of hippocampal calcifications. One measure per patient, only the most severe score, was used. Logistic regression was used to identify risk factors for hippocampal calcifications, and linear regression was used for the association between hippocampal calcifications (patient level) and cognitive function. Results A total of 1991 patients (mean age, 78 years; range, 45-96 years) were included. The mean age of women was 79 years (range, 47-96 years), and the mean age of men was 77 years (range, 45-95 years). Of the 1991 patients, 380 (19.1%) had hippocampal calcifications. Older age (odds ratio [OR] per year, 1.05; 95% confidence interval [CI]: 1.03, 1.06), diabetes mellitus (OR, 1.50; 95% CI: 1.12, 2.00), and smoking (OR, 1.49; 95% CI: 1.05, 2.10) were associated with the presence of hippocampal calcifications. No associations were found between presence and severity of hippocampal calcifications and cognitive function. Conclusion Older age, diabetes mellitus, and smoking were associated with an increased risk of hippocampal calcifications. A greater degree of hippocampal calcifications was not associated with lower cognitive function in patients with memory complaints.

Computed Tomography Perfusion Derived Blood-Brain Barrier Permeability Does Not Yet Improve Prediction of Hemorrhagic Transformation.

INTRODUCTION: Hemorrhagic transformation (HT) in acute ischemic stroke can occur as a result of reperfusion treatment. While withholding treatment may be warranted in patients with increased risk of HT, prediction of HT remains difficult. Nonlinear regression analysis can be used to estimate blood-brain barrier permeability (BBBP). The aim of this study was to identify a combination of clinical and imaging variables, including BBBP estimations, that can predict HT. MATERIALS AND METHODS: From the Dutch acute stroke study, 545 patients treated with intravenous recombinant tissue plasminogen activator and/or intra-arterial treatment were selected, with available admission extended computed tomography (CT) perfusion and follow-up imaging. Patient admission treatment characteristics and CT imaging parameters regarding occlusion site, stroke severity, and BBBP were recorded. HT was assessed on day 3 follow-up imaging. The association between potential predictors and HT was analyzed using univariate and multivariate logistic regression. To compare the added value of BBBP, areas under the curve (AUCs) were created from 2 models, with and without BBBP. RESULTS: HT occurred in 57 patients (10%). In univariate analysis, older age (OR 1.03, 95% CI 1.006-1.05), higher admission National Institutes of Health Stroke Scale (NIHSS; OR 1.13, 95% CI 1.08-1.18), higher clot burden (OR 1.28, 95% CI 1.16-1.41), poor collateral score (OR 3.49, 95% CI 1.85-6.58), larger Alberta Stroke Program Early CT Score cerebral blood volume deficit size (OR 1.26, 95% CI 1.14-1.38), and increased BBBP (OR 2.22, 95% CI 1.46-3.37) were associated with HT. In multivariate analysis with age and admission NIHSS, the addition of BBBP did not improve the AUC compared to both independent predictors alone (AUC 0.77, 95% CI 0.71-0.83). CONCLUSION: BBBP predicts HT but does not improve prediction with age and admission NIHSS.

Thoracic aorta calcification but not inflammation is associated with increased cardiovascular disease risk: results of the CAMONA study.

PURPOSE: Arterial inflammation and vascular calcification are regarded as early prognostic markers of cardiovascular disease (CVD). In this study we investigated the relationship between CVD risk and arterial inflammation (18F-FDG PET/CT imaging), vascular calcification metabolism (Na18F PET/CT imaging), and vascular calcium burden (CT imaging) of the thoracic aorta in a population at low CVD risk. METHODS: Study participants underwent blood pressure measurements, blood analyses, and 18F-FDG and Na18F PET/CT imaging. In addition, the 10-year risk for development of CVD, based on the Framingham risk score (FRS), was estimated. CVD risk was compared across quartiles of thoracic aorta 18F-FDG uptake, Na18F uptake, and calcium burden on CT. RESULTS: A total of 139 subjects (52 % men, mean age 49 years, age range 21 - 75 years, median FRS 6 %) were evaluated. CVD risk was, on average, 3.7 times higher among subjects with thoracic aorta Na18F uptake in the highest quartile compared with those in the lowest quartile of the distribution (15.5 % vs. 4.2 %; P < 0.001). CVD risk was on average, 3.7 times higher among subjects with a thoracic aorta calcium burden on CT in the highest quartile compared with those in the lowest two quartiles of the distribution (18.0 % vs. 4.9 %; P < 0.001). CVD risk was similar in subjects in all quartiles of thoracic aorta 18F-FDG uptake. CONCLUSION: Our findings indicate that an unfavourable CVD risk profile is associated with marked increases in vascular calcification metabolism and vascular calcium burden of the thoracic aorta, but not with arterial inflammation.

Do Lacunar Infarcts Have Different Aetiologies? Risk Factor Profiles of Lacunar Infarcts in Deep White Matter and Basal Ganglia: The Second Manifestations of ARTerial Disease-Magnetic Resonance Study.

BACKGROUND: Evidence suggests that lacunar infarcts have different etiologies, possibly related to their anatomical location and vascular territory. We investigated the risk factor profiles of patients with new lacunar infarcts in the basal ganglia and deep white matter. METHODS: Within the Second Manifestations of ARTerial disease-Magnetic Resonance study, a prospective cohort on brain changes on MRI in patients with symptomatic atherosclerotic disease, 679 patients (57 ± 9 years) had vascular screening and MRI at baseline and after a mean follow-up of 3.9 years. We investigated the association between vascular risk factors at baseline and appearance of new lacunar infarcts in the basal ganglia and deep white matter at follow-up. RESULTS: New lacunar infarcts appeared in 44 patients in the basal ganglia and in 37 patients in the deep white matter. In multivariable analysis, older age, history of cerebrovascular disease, and baseline white matter hyperintensity (WMH) volume were associated with increased risk of new lacunar infarcts in both locations. Hyperhomocysteinemia was associated with increased risk of lacunar infarcts in the basal ganglia (relative risk [RR] 2.0; 95% CI 1.0-4.2), whereas carotid stenosis >70% (RR 2.5; 95% CI 1.2-5.0), smoking (per 10 pack-year: RR 1.1; 95% CI 1.0-1.3), hypertension (RR 3.4; 95% CI 1.2-9.7), and progression of WMH volume (RR 2.4; 95% CI 1.1-5.2) were associated with increased risk of lacunar infarcts in the deep white matter. CONCLUSIONS: The different risk factor profiles for new lacunar infarcts in basal ganglia and deep white matter indicate different etiologies. The independent association between progression of WMH and new deep white matter lacunar infarcts suggest a common etiology for these radiological abnormalities.

Predominance of Nonatherosclerotic Internal Elastic Lamina Calcification in the Intracranial Internal Carotid Artery.

BACKGROUND AND PURPOSE: Calcification of the intracranial internal carotid artery (iICA) is an independent risk factor for stroke. These calcifications are generally seen as manifestation of atherosclerosis, but histological investigations are limited. The aim of this study is to determine whether calcifications in the iICA are present in atherosclerotic plaques, or in other parts of the arterial wall. METHODS: Thirty-nine iICAs were histologically assessed, using digital microscopy to quantify the amount of calcification in the different layers of the arterial wall. RESULTS: Calcifications were found in the intima, around the internal elastic lamina and in the medial layer of the arterial wall. In 71% of the arteries, internal elastic lamina calcification contributed most to the total calcified cross-sectional surface area. Internal elastic lamina calcification was unrelated to the occurrence of atherosclerotic intimal lesions. Intimal calcifications were most often associated with atherosclerotic lesions, but also many noncalcified atherosclerotic lesions were found. CONCLUSIONS: In the iICA, calcifications are predominantly present around the internal elastic lamina, suggesting that this nonatherosclerotic type of calcification contributes to the previously observed increased risk of stroke in patients with iICA calcifications.

CT angiography and CT perfusion improve prediction of infarct volume in patients with anterior circulation stroke.

INTRODUCTION: We investigated whether baseline CT angiography (CTA) and CT perfusion (CTP) in acute ischemic stroke could improve prediction of infarct presence and infarct volume on follow-up imaging. METHODS: We analyzed 906 patients with suspected anterior circulation stroke from the prospective multicenter Dutch acute stroke study (DUST). All patients underwent baseline non-contrast CT, CTA, and CTP and follow-up non-contrast CT/MRI after 3 days. Multivariable regression models were developed including patient characteristics and non-contrast CT, and subsequently, CTA and CTP measures were added. The increase in area under the curve (AUC) and R (2) was assessed to determine the additional value of CTA and CTP. RESULTS: At follow-up, 612 patients (67.5%) had a detectable infarct on CT/MRI; median infarct volume was 14.8 mL (interquartile range (IQR) 2.8-69.6). Regarding infarct presence, the AUC of 0.82 (95% confidence interval (CI) 0.79-0.85) for patient characteristics and non-contrast CT was improved with addition of CTA measures (AUC 0.85 (95% CI 0.82-0.87); p < 0.001) and was even higher after addition of CTP measures (AUC 0.89 (95% CI 0.87-0.91); p < 0.001) and combined CTA/CTP measures (AUC 0.89 (95% CI 0.87-0.91); p < 0.001). For infarct volume, adding combined CTA/CTP measures (R (2) = 0.58) was superior to patient characteristics and non-contrast CT alone (R (2) = 0.44) and to addition of CTA alone (R (2) = 0.55) or CTP alone (R (2) = 0.54; all p < 0.001). CONCLUSION: In the acute stage, CTA and CTP have additional value over patient characteristics and non-contrast CT for predicting infarct presence and infarct volume on follow-up imaging. These findings could be applied for patient selection in future trials on ischemic stroke treatment.

Longitudinal relationship between cerebral small-vessel disease and cerebral blood flow: the second manifestations of arterial disease-magnetic resonance study.

BACKGROUND AND PURPOSE: Cerebral small-vessel disease and cerebral blood flow (CBF) are interrelated. However, the direction of the relationship is unknown, and longitudinal studies are scarce. We investigated the longitudinal relationship between CBF and white matter hyperintensities (WMHs) and lacunes, as representatives of cerebral small-vessel disease, in patients with manifest arterial disease. METHODS: Within the Second Manifestations of Arterial Disease-Magnetic Resonance (SMART-MR) study, 1.5T brain magnetic resonance imaging, including an MR angiography, was obtained at baseline and after on ≈3.9 years of follow-up in 575 patients with manifest arterial disease (mean age, 57±10 years). Longitudinal associations of WMHs and lacunes with parenchymal CBF (pCBF; per 100-mL brain volume) were estimated using regression analyses, adjusted for age, sex, follow-up time, and baseline brain measures. RESULTS: Baseline pCBF was not associated with progression of WMHs and lacunes over time. However, periventricular and deep WMHs at baseline were associated with decline in pCBF; mean (95% confidence interval) decline in pCBF per % intracranial volume increase in periventricular and deep WMH volume was -0.70 (-1.40 to -0.00) and -1.01 (-1.64 to -0.38) mL/min per 100-mL brain volume, respectively. These associations were partly explained by cardiovascular risk factors but remained significant for deep WMHs (mean decline [95% confidence interval] in pCBF per % intracranial volume increase in deep WMH volume was -0.92 [-1.56 to -0.28] mL/min per 100-mL brain volume). Lacunes were not associated with change in pCBF. CONCLUSIONS: In patients with manifest arterial disease, baseline periventricular and deep WMH volumes were associated with decline in pCBF over time, but baseline pCBF was not associated with progression of WMHs and lacunes over time.

Airway wall thickness associated with forced expiratory volume in 1 second decline and development of airflow limitation.

Airway wall thickness and emphysema contribute to airflow limitation. We examined their association with lung function decline and development of airflow limitation in 2021 male smokers with and without airflow limitation. Airway wall thickness and emphysema were quantified on chest computed tomography and expressed as the square root of wall area of a 10-mm lumen perimeter (Pi10) and the 15th percentile method (Perc15), respectively. Baseline and follow-up (median (interquartile range) 3 (2.9-3.1) years) spirometry was available. Pi10 and Perc15 correlated with baseline forced expiratory volume in 1 s (FEV1) (r= -0.49 and 0.11, respectively (p<0.001)). Multiple linear regression showed that Pi10 and Perc15 at baseline were associated with a lower FEV1 after follow-up (p<0.05). For each sd increase in Pi10 and decrease in Perc15 the FEV1 decreased by 20 mL and 30.2 mL, respectively. The odds ratio for developing airflow limitation after 3 years was 2.45 for a 1-mm higher Pi10 and 1.46 for a 10-HU lower Perc15 (p<0.001). A greater degree of airway wall thickness and emphysema was associated with a higher FEV1 decline and development of airflow limitation after 3 years of follow-up.

Towards a close computed tomography monitoring approach for screen detected subsolid pulmonary nodules?

Pulmonary subsolid nodules (SSNs) have a high likelihood of malignancy, but are often indolent. A conservative treatment approach may therefore be suitable. The aim of the current study was to evaluate whether close follow-up of SSNs with computed tomography may be a safe approach. The study population consisted of participants of the Dutch-Belgian lung cancer screening trial (Nederlands Leuvens Longkanker Screenings Onderzoek; NELSON). All SSNs detected during the trial were included in this analysis. Retrospectively, all persistent SSNs and SSNs that were resected after first detection were segmented using dedicated software, and maximum diameter, volume and mass were measured. Mass doubling time (MDT) was calculated. In total 7135 volunteers were included in the current analysis. 264 (3.3%) SSNs in 234 participants were detected during the trial. 147 (63%) of these SSNs in 126 participants disappeared at follow-up, leaving 117 persistent or directly resected SSNs in 108 (1.5%) participants available for analysis. The median follow-up time was 95 months (range 20-110 months). 33 (28%) SSNs were resected and 28 of those were (pre-) invasive. None of the non-resected SSNs progressed into a clinically relevant malignancy. Persistent SSNs rarely developed into clinically manifest malignancies unexpectedly. Close follow-up with computed tomography may be a safe option to monitor changes.

Completeness of the circle of Willis and risk of ischemic stroke in patients without cerebrovascular disease.

INTRODUCTION: We investigated circle of Willis (CoW) completeness in relation to the risk of future ischemic stroke in patients without prior cerebrovascular disease. METHODS: We included 976 patients with atherosclerotic disease, but no previous TIA/stroke, from the Second Manifestations of ARTerial disease (SMART) study. All patients underwent MR angiography of the CoW. Cox regression was used to determine whether anterior CoW completeness (anterior communicating artery or A1 segments) and posterior CoW completeness (posterior communicating arteries or P1 segments) were related to future stroke, and whether CoW completeness influenced the relation between internal carotid artery (ICA) stenosis/occlusion and future stroke. RESULTS: Thirty patients (3.1 %) had ischemic stroke after 9.2 ± 3.0 years of follow-up. Twenty-four patients (80 %) had anterior circulation stroke. An incomplete anterior CoW was related to future anterior circulation stroke (HR 2.8 (95 % CI 1.3-6.3); p = 0.01), whereas a one-sided and two-sided incomplete posterior CoW were not (HR 2.2 (95 % CI 0.7-7.1; p = 0.19) and 1.9 (95 % CI 0.6-5.9; p = 0.29), respectively). In stratified analyses, patients with an incomplete anterior CoW had the highest risk of future anterior circulation stroke when they also had a one-sided (HR 7.0 (95 % CI 1.3-38.2; p = 0.02)) or two-sided incomplete posterior CoW (HR 5.4 (95 % CI 1.0-27.8; p = 0.04). CoW completeness did not change the relation between asymptomatic ICA stenosis/occlusion and future ischemic stroke (p = 0.68). CONCLUSIONS: An incomplete anterior CoW combined with an incomplete posterior CoW is related to future anterior circulation stroke. CoW completeness has no large effect on the relation between asymptomatic ICA stenosis/occlusion and future stroke.

Radiation dose reduction in cerebral CT perfusion imaging using iterative reconstruction.

OBJECTIVES: To investigate whether iterative reconstruction (IR) in cerebral CT perfusion (CTP) allows for 50% dose reduction while maintaining image quality (IQ). METHODS: A total of 48 CTP examinations were reconstructed into a standard dose (150 mAs) with filtered back projection (FBP) and half-dose (75 mAs) with two strengths of IR (middle and high). Objective IQ (quantitative perfusion values, contrast-to-noise ratio (CNR), penumbra, infarct area and penumbra/infarct (P/I) index) and subjective IQ (diagnostic IQ on a four-point Likert scale and overall IQ binomial) were compared among the reconstructions. RESULTS: Half-dose CTP with high IR level had, compared with standard dose with FBP, similar objective (grey matter cerebral blood volume (CBV) 4.4 versus 4.3 mL/100 g, CNR 1.59 versus 1.64 and P/I index 0.74 versus 0.73, respectively) and subjective diagnostic IQ (mean Likert scale 1.42 versus 1.49, respectively). The overall IQ in half-dose with high IR level was scored lower in 26-31%. Half-dose with FBP and with the middle IR level were inferior to standard dose with FBP. CONCLUSION: With the use of IR in CTP imaging it is possible to examine patients with a half dose without significantly altering the objective and diagnostic IQ. The standard dose with FBP is still preferable in terms of subjective overall IQ in about one quarter of patients. KEY POINTS: • Computed tomography perfusion (CTP) is increasingly important in ischaemia imaging. • Radiation exposure of CTP is a drawback. • Iterative reconstruction (IR) allows reduction of radiation dose in unenhanced head CT. • CTP IR enables 50% dose reduction without altering objective and diagnostic quality.

Prediction of outcome in patients with suspected acute ischaemic stroke with CT perfusion and CT angiography: the Dutch acute stroke trial (DUST) study protocol.

BACKGROUND: Prediction of clinical outcome in the acute stage of ischaemic stroke can be difficult when based on patient characteristics, clinical findings and on non-contrast CT. CT perfusion and CT angiography may provide additional prognostic information and guide treatment in the early stage. We present the study protocol of the Dutch acute Stroke Trial (DUST). The DUST aims to assess the prognostic value of CT perfusion and CT angiography in predicting stroke outcome, in addition to patient characteristics and non-contrast CT. For this purpose, individualised prediction models for clinical outcome after stroke based on the best predictors from patient characteristics and CT imaging will be developed and validated. METHODS/DESIGN: The DUST is a prospective multi-centre cohort study in 1500 patients with suspected acute ischaemic stroke. All patients undergo non-contrast CT, CT perfusion and CT angiography within 9 hours after onset of the neurological deficits, and, if possible, follow-up imaging after 3 days. The primary outcome is a dichotomised score on the modified Rankin Scale, assessed at 90 days. A score of 0-2 represents good outcome, and a score of 3-6 represents poor outcome. Three logistic regression models will be developed, including patient characteristics and non-contrast CT (model A), with addition of CT angiography (model B), and CT perfusion parameters (model C). Model derivation will be performed in 60% of the study population, and model validation in the remaining 40% of the patients. Additional prognostic value of the models will be determined with the area under the curve (AUC) from the receiver operating characteristic (ROC) curve, calibration plots, assessment of goodness-of-fit, and likelihood ratio tests. DISCUSSION: This study will provide insight in the added prognostic value of CTP and CTA parameters in outcome prediction of acute stroke patients. The prediction models that will be developed in this study may help guide future treatment decisions in the acute stage of ischaemic stroke.

Inter-and intrarater agreement of Computed Tomographic brain calcification scoring in Primary Familial Brain Calcification.

BACKGROUND AND PURPOSE: The Total Calcification Score (TCS) is a visual rating scale to measure Primary Familial Brain Calcification (PFBC) related calcification severity on Computed Tomography (CT). We investigated the inter-and intrarater agreement of a modified TCS. MATERIALS AND METHODS: Patients aged ≥18 years with PFBC or Fahr's syndrome who visited the outpatient clinic of a Dutch academic hospital were included. The TCS was modified, for example by adding hippocampal calcification, and ranged from 0 to 95 points. Fifteen raters evaluated all CTs, of whom three evaluated the CTs twice. Their Entrustable Professional Activity (EPA) level ranged from II (medical student) to V (neuroradiologist). Agreement was assessed using the intraclass correlation coefficient (ICC) for the total score. Kendall's W and weighted Cohen's Kappa were used to determine the inter- and intrarater agreement for individual locations, respectively. RESULTS: Forty patients were included (mean age 60 years, 53% female). The median modified TCS was 34 (range 4-76). For all EPA levels, the interrater agreement of the modified TCS was excellent (ICC=0.97 (95% CI 0.95-0.98)). Kendall's W's were good to excellent for commonly affected locations, but poor to moderate for less commonly affected locations for raters with lower levels of expertise. The intrarater agreement of the modified TCS was excellent. Kappa's of most locations were substantial to almost perfect. CONCLUSIONS: The modified TCS can be used with excellent reproducibility of the overall amount of brain calcifications and with limited training, although for some individual calcification locations more expertise is needed. ABBREVIATIONS: CI, Confidence Interval; CT, Computed Tomography; EPA, Entrustable Professional Activity; IBGC, Idiopathic Basal Ganglia Calcification; ICC, Intraclass Correlation Coefficient; IQR, Interquartile Range; PFBC, Primary Familial Brain Calcification; SD, Standard Deviation, TCS, Total Calcification Score; UMCU, University Medical Center Utrecht.

Optimisation of vascular input and output functions in CT-perfusion imaging using 256(or more)-slice multidetector CT.

OBJECTIVES: To evaluate the accuracy and reproducibility of CT-perfusion (CTP) by finding the optimal artery for the arterial input function (AIF) and re-evaluating the necessity of the venous output function (VOF). METHODS: Forty-four acute ischaemic stroke patients who underwent non-enhanced CT, CTP and CT-angiography using 256-slice multidetector computed tomography (MDCT) were evaluated. The anterior cerebral artery (ACA), middle cerebral artery (MCA), internal carotid artery (ICA) and basilar artery were selected as the AIF. Subsequently the resulting area under the time-enhancement curve of the AIF (AUCAIF) and quantitative perfusion measurements were analysed by repeated measures ANOVA and subsequently the paired t test. To evaluate reproducibility we examined if the VOF could be deleted by comparing the perfusion measurements using versus not using the VOF (paired t test). RESULTS: The AUCAIF and perfusion measurements resulting from the different AIFs showed significant group differences (all P < 0.0001). The ICA had the largest AUCAIF and resulted in the highest mean transient time (MTT) and lowest cerebral blood flow (CBF), whereas the basilar artery showed the lowest cerebral blood volume (CBV). Not using the VOF showed significantly higher CBV and CBF in 66 % of patients on the ipsilateral (P < 0.0001 and P = 0.007, respectively) and contralateral hemisphere (P < 0.0001 and P = 0.019, respectively). CONCLUSION: Selecting the ICA as the AIF and continuing the use of the VOF would improve the accuracy of CTP. KEY POINTS: • Perfusion imaging is an increasingly important aspect of multidetector computed tomography (MDCT). • Vascular input functions were evaluated for CT-perfusion using 256-slice MDCT. • Selecting different arterial input functions (AIFs) leads to variation in quantitative values. • Using the internal carotid artery for AIF provides optimal perfusion values. • Deleting the venous output function would be detrimental for validity.

Homocysteine, progression of ventricular enlargement, and cognitive decline: the Second Manifestations of ARTerial disease-Magnetic Resonance study.

BACKGROUND: Homocysteine may be a modifiable risk factor for cognitive decline and brain atrophy, particularly in older persons. We examined whether homocysteine increased the risk for cognitive decline and brain atrophy, and evaluated the modifying effect of age. METHODS: Within the Second Manifestations of ARTerial disease-Magnetic Resonance study-a prospective cohort study among patients with atherosclerotic disease-longitudinal analyses were performed in 663 patients (mean age: 57 ± 9 years; follow-up: 3.9 ± 0.4 years). At baseline and follow-up, brain segmentation on magnetic resonance imaging was used to quantify relative (%) cortical, ventricular, and global brain volumes, and z-scores of memory and executive functioning were calculated. Linear regression analysis was used to estimate associations of homocysteine (per standard deviation increase) and hyperhomocysteinemia (HHCY) with brain volumes, memory, and executive functioning at follow-up, adjusted for baseline brain volume, memory, and executive functioning, respectively, and age, sex, and vascular risk factors. Furthermore, interaction terms between homocysteine and age (continuous) were added. RESULTS: Significant interactions were observed between total plasma homocysteine (tHcy) and age with cortical, ventricular, and global brain volume (for all three measures: P < .05), and between HHCY and age with executive functioning (P = .04), and results were stratified by age. In patients aged ≥65 years, increasing tHcy level and HHCY were significantly associated with progression of ventricular enlargement (B = 0.07%, 95% confidence interval [CI]: 0.01% to 0.13% and B = 0.16%, 95% CI: 0.01% to 0.31%, respectively) and with a decline in executive function (B = -0.29, 95% CI: -0.54 to -0.04 and B = -0.84, 95% CI: -1.37 to -0.32, respectively). CONCLUSION: Elevated tHcy was related to progression of ventricular enlargement and increased the risk for a decline in executive functioning in older persons.

Holmium-166 radioembolisation in patients with unresectable, chemorefractory liver metastases (HEPAR trial): a phase 1, dose-escalation study.

BACKGROUND: The efficacy of radioembolisation for the treatment of liver tumours depends on the selective distribution of radioactive microspheres to tumorous tissue. The distribution of holmium-166 ((166)Ho) poly(L-lactic acid) microspheres can be visualised in vivo by both single-photon-emission CT (SPECT) and MRI. In this phase 1 clinical trial, we aimed to assess the safety and the maximum tolerated radiation dose (MTRD) of (166)Ho-radioembolisation in patients with liver metastases. METHODS: Between Nov 30, 2009, and Sept 19, 2011, patients with unresectable, chemorefractory liver metastases were enrolled in the Holmium Embolization Particles for Arterial Radiotherapy (HEPAR) trial. Patients were treated with intra-arterial (166)Ho-radioembolisation in cohorts of three patients, with escalating aimed whole-liver absorbed doses of 20, 40, 60, and 80 Gy. Cohorts were extended to a maximum of six patients if dose-limiting toxicity occurred. Patients were assigned a dose in the order of study entry, with dose escalation until dose-limiting toxicity was encountered in at least two patients of a dose cohort. Clinical or laboratory toxicities were scored according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3.0. The primary endpoint was the MTRD. Analyses were per protocol. This study is registered with ClinicalTrials.gov, number NCT01031784. FINDINGS: 15 patients underwent (166)Ho-radioembolisation at doses of 20 Gy (n=6), 40 Gy (n=3), 60 Gy (n=3), and 80 Gy (n=3). Mean estimated whole-liver absorbed doses were 18 Gy (SD 2) for the 20 Gy cohort, 35 Gy (SD 1) for the 40 Gy cohort, 58 Gy (SD 3) for the 60 Gy cohort, and 73 Gy (SD 4) for the 80 Gy cohort. The 20 Gy cohort was extended to six patients because of the occurrence of dose-limiting toxicity in one patient (pulmonary embolism). In the 80 Gy cohort, dose-limiting toxicity occurred in two patients: grade 4 thrombocytopenia, grade 3 leucopenia, and grade 3 hypoalbuminaemia in one patient, and grade 3 abdominal pain in another patient. The MTRD was identified as 60 Gy. The most frequently encountered laboratory toxicities (including grade 1) were lymphocytopenia, hypoalbuminaemia, raised alkaline phosphatase, raised aspartate aminotransferase, and raised gamma-glutamyltransferase, which were all noted in 12 of 15 patients. Stable disease or partial response regarding target lesions was achieved in 14 of 15 patients (93%, 95% CI 70-99) at 6 weeks and nine of 14 patients (64%, 95% CI 39-84) at 12 weeks after radioembolisation. Compared with baseline, the average global health status and quality of life scale score at 6 weeks after treatment had decreased by 13 points (p=0·053) and by 14 points at 12 weeks (p=0·048). In all patients, technetium-99m ((99m)Tc)-macro-aggregated albumin SPECT, (166)Ho scout dose SPECT, and (166)Ho treatment dose SPECT showed similar patterns of the presence or absence of extrahepatic deposition of activity. INTERPRETATION: (166)Ho-radioembolisation is feasible and safe for the treatment of patients with unresectable and chemorefractory liver metastases and enables image-guided treatment. Clinical (166)Ho-radioembolisation should be done with an aimed whole-liver absorbed dose of 60 Gy.