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.

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.).

Downgrading of Breast Masses Suspicious for Cancer by Using Optoacoustic Breast Imaging.

Purpose To assess the ability of optoacoustic (OA) ultrasonography (US) to help correctly downgrade benign masses classified as Breast Imaging Reporting and Data System (BI-RADS) 4a and 4b to BI-RADS 3 or 2. Materials and Methods OA/US technology uses laser light to detect relative amounts of oxygenated and deoxygenated hemoglobin in and around suspicious breast masses. In this prospective, multicenter study, results of 209 patients with 215 breast masses classified as BI-RADS 4a or 4b at US are reported. Patients were enrolled between 2015 and 2016. Masses were first evaluated with US with knowledge of previous clinical information and imaging results, and from this information a US imaging-based probability of malignancy (POM) and BI-RADS category were assigned to each mass. The same masses were then re-evaluated at OA/US. During the OA/US evaluation, radiologists scored five OA/US features, and then reassigned an OA/US-based POM and BI-RADS category for each mass. BI-RADS downgrade and upgrade percentages at OA/US were assessed by using a weighted sum of the five OA feature scores. Results At OA/US, 47.9% (57 of 119; 95% CI: 0.39, 0.57) of benign masses classified as BI-RADS 4a and 11.1% (three of 27; 95% CI: 0.03, 0.28) of masses classified as BI-RADS 4b were correctly downgraded to BI-RADS 3 or 2. Two of seven malignant masses classified as BI-RADS 4a at US were incorrectly downgraded, and one of 60 malignant masses classified as BI-RADS 4b at US was incorrectly downgraded for a total of 4.5% (three of 67; 95% CI: 0.01, 0.13) false-negative findings. Conclusion At OA/US, benign masses classified as BI-RADS 4a could be downgraded in BI-RADS category, which would potentially decrease biopsies negative for cancer and short-interval follow-up examinations, with the limitation that a few masses may be inappropriately downgraded.

MR Imaging as an Additional Screening Modality for the Detection of Breast Cancer in Women Aged 50-75 Years with Extremely Dense Breasts: The DENSE Trial Study Design.

Women with extremely dense breasts have an increased risk of breast cancer and lower mammographic tumor detectability. Nevertheless, in most countries, these women are currently screened with mammography only. Magnetic resonance (MR) imaging has the potential to improve breast cancer detection at an early stage because of its higher sensitivity. However, MR imaging is more expensive and is expected to be accompanied by an increase in the number of false-positive results and, possibly, an increase in overdiagnosis. To study the additional value of MR imaging, a randomized controlled trial (RCT) design is needed in which one group undergoes mammography and the other group undergoes mammography and MR imaging. With this design, it is possible to determine the proportion of interval cancers within each study arm. For this to be an effective screening strategy, the additional cancers detected at MR imaging screening must be accompanied by a subsequent reduction in interval cancers. The Dense Tissue and Early Breast Neoplasm Screening, or DENSE, trial is a multicenter RCT performed in the Dutch biennial population-based screening program (subject age range, 50-75 years). The study was approved by the Dutch Minister of Health, Welfare and Sport. In this study, mammographic density is measured by using a fully automated volumetric method. Participants with extremely dense breasts (American College of Radiology breast density category 4) and a negative result at mammography (Breast Imaging Recording and Data System category 1 or 2) are randomly assigned to undergo additional MR imaging (n = 7237) or to be treated according to current practice (n = 28 948). Participants provide written informed consent before the MR imaging examination, which consists of dynamic breast MR imaging with gadolinium-based contrast medium and is intended to be performed for three consecutive screening rounds. The primary outcome is the difference in the proportions of interval cancers between the study arms. Secondary outcomes are the number of MR imaging screening-detected cancers, proportions of false-positive results, diagnostic yield of MR imaging, tumor characteristics, quality of life, and cost effectiveness.

Incremental value of arterial and equilibrium phase compared to hepatic venous phase CT in the preoperative staging of colorectal liver metastases: an evaluation with different reference standards.

PURPOSE: To evaluate the incremental value of arterial and equilibrium phase compared to hepatic venous phase multidetector row CT (MDCT) in the preoperative staging of colorectal liver metastases (CLM) and to determine the influence of the reference standard. MATERIALS AND METHODS: Fifty-three consecutive CLM patients underwent 16 detector row CT in hepatic arterial, venous, and equilibrium phase before surgery between March 2003 and January 2007. Detected lesions were characterized by three independent radiologists. The reference standard consisted of intraoperative palpation and ultrasound of the liver, and histopathological examination of the resected specimen. Additionally, data of follow-up CT was added. Statistical analysis was performed on a per-lesion basis. RESULTS: According to the reference standard 251 lesions were present, of which 203 (81%) were malignant (mean size: 29.4 ± 22.5 mm), and 41 (16%) were benign (mean size: 8.3 ± 7.7 mm). Sensitivity rates for CLM were comparable between triphasic and hepatic venous phase CT (P>0.05). Sensitivity for the detection of CLM lowered from 60-77% to 52-68% when follow-up CT was added to the reference standard. CONCLUSION: Arterial and equilibrium phase CT have no incremental value compared to hepatic venous phase MDCT in the detection of CLM. Sensitivity rates are, however, influenced by the type of reference standard used.

Automatic segmentation of different-sized white matter lesions by voxel probability estimation.

A new method for fully automated segmentation of white matter lesions (WMLs) on cranial MR imaging is presented. The algorithm uses five types of regular MRI-scans. It is based on a K-Nearest Neighbor (KNN) classification technique, which builds a feature space from voxel intensity features and spatial information. The technique generates images representing the probability per voxel being part of a WML. By application of thresholds on these probability maps binary segmentations can be produced. ROC-curves show that the segmentations achieve a high sensitivity and specificity. Three similarity measures, the similarity index (SI), the overlap fraction (OF) and the extra fraction (EF), are calculated for evaluation of the results and determination of the optimal threshold on the probability map. Investigation of the relation between the total lesion volume and the similarity measures shows that the method performs well for lesions larger than 2 cc. The maximum SI per patient is correlated to the total WML volume. No significant relation between the lesion volume and the optimal threshold has been observed. The probabilistic equivalents of the SI, OF en EF (PSI, POF and PEF) allow direct evaluation of the probability maps, which provides a strong tool for comparison of different classification results. A significant correlation between the lesion volume and the PSI and the PEF has been noticed. This method for automated WML segmentation is applicable to lesions of different sizes and shapes, and reaches an accuracy that is comparable to existing methods for multiple sclerosis lesion segmentation. Furthermore, it is suitable for detection of WMLs in large and longitudinal population studies.

Elevated levels of plasma homocysteine are associated with neurotoxicity.

OBJECTIVE: The aim of the present study is to investigate whether increased plasma homocysteine (tHcy) has an effect on the cerebral metabolic concentrations, reflecting neurotoxicity, measured with Magnetic Resonance Spectroscopy (MRS). METHODS: One hundred and thirteen patients had a MRS investigation of the brain and the concentration of N-acetyl-aspartate (NAA), choline and creatine was measured and fasting plasma tHcy was assessed. We used linear regression models to investigate the association between tHcy and cerebral metabolic concentrations. RESULTS: We found that tHcy is associated with cerebral NAA (B = -0.09 mmol/l (95% CI, -0.17 to -0.00)) and with creatine (B = -0.09 mmol/l (95% CI, -0.16 to -0.02)) per 1 micromol/l increase tHcy. Patients with a tHcy >/=14 micromol/l had a lower concentration cerebral of NAA (P < 0.05) and creatine (P < 0.01) compared with patients with a tHcy <14 micromol/l. No significant association was found for the cerebral choline. CONCLUSION: Elevated levels of tHcy were associated with low concentrations of cerebral NAA and creatine, independent of renal function or the presence of atherosclerotic disease. These preliminary results suggest that tHcy has a neurotoxic effect in vivo.

Probabilistic segmentation of white matter lesions in MR imaging.

A new method has been developed for fully automated segmentation of white matter lesions (WMLs) in cranial MR imaging. The algorithm uses information from T1-weighted (T1-w), inversion recovery (IR), proton density-weighted (PD), T2-weighted (T2-w) and fluid attenuation inversion recovery (FLAIR) scans. It is based on the K-Nearest Neighbor (KNN) classification technique that builds a feature space from voxel intensities and spatial information. The technique generates images representing the probability per voxel being part of a WML. By application of thresholds on these probability maps, binary segmentations can be obtained. ROC curves show that the segmentations achieve both high sensitivity and specificity. A similarity index (SI), overlap fraction (OF) and extra fraction (EF) are calculated for additional quantitative analysis of the result. The SI is also used for determination of the optimal probability threshold for generation of the binary segmentation. Using probabilistic equivalents of the SI, OF and EF, the probability maps can be evaluated directly, providing a powerful tool for comparison of different classification results. This method for automated WML segmentation reaches an accuracy that is comparable to methods for multiple sclerosis (MS) lesion segmentation and is suitable for detection of WMLs in large and longitudinal population studies.

Prevalence and volume of internal border zone lesions in patients with impaired cerebral carbon dioxide vasomotor reactivity: a follow-up study.

BACKGROUND: The precise etiology of border zone infarcts is controversial. Hemodynamic impairment due to obstructive disease of the internal carotid artery (ICA) is suggested as a cause of border zone infarcts. OBJECTIVE: To investigate changes in prevalence and volume of ischemic border zone lesions over time in patients with occlusive disease of the ICA after 1 year of follow-up. DESIGN: Follow-up study. SETTING: Referral center. PATIENTS: Fifty-eight patients with an occlusion of the ICA were included. At baseline, ischemic lesions were classified on magnetic resonance imaging, and vasomotor reactivity was assessed with transcranial Doppler ultrasonography with carbon dioxide challenge. MAIN OUTCOME MEASURES: Changes in prevalence and volume of ischemic lesions were monitored and were correlated with carbon dioxide reactivity at baseline. RESULTS: No significant changes in the prevalence of any infarct types were observed after 1 year of follow-up in the hemispheres ipsilateral or contralateral to the ICA occlusion. However, in hemispheres ipsilateral to an occluded ICA, we found an increase in mean volume of internal border zone infarcts (P =.002). In hemispheres with a low carbon dioxide reactivity, we found an increase in mean volume of internal border zone lesions after 1 year (carbon dioxide reactivity,

Association between impaired carbon dioxide reactivity and ischemic lesions in arterial border zone territories in patients with unilateral internal carotid artery occlusion.

CONTEXT: Ischemic lesions in patients with internal carotid artery (ICA) steno-occlusive disease can be categorized on the basis of their location and presumed cause: external border zone infarcts, internal border zone infarcts, cortical infarcts, lacunar infarcts, and periventricular lesions. OBJECTIVE: To evaluate the association between the prevalence and size of ischemic lesions and cerebral vasomotor reactivity in patients with unilateral occlusion of the ICA. DESIGN: Cross-sectional study. SETTING: Referral center. PATIENTS: Seventy consecutive patients were included in this study. All patients had a transient or minor disabling retinal or cerebral ischemia that was associated with unilateral occlusion of the ICA. Ischemic lesions on magnetic resonance imaging were identified on hard copies, and volume measurements were obtained by a magnetic resonance workstation. Vasomotor reactivity was assessed with transcranial Doppler ultrasonography with carbon dioxide challenge. MAIN OUTCOME MEASURES: Prevalence and size of ischemic lesions. RESULTS: In the hemisphere ipsilateral to the ICA occlusion, we found an increased prevalence of internal border zone infarcts (P =.01), external borders zone infarcts (P<.001), and territorial infarcts (P =.02) compared with the contralateral hemisphere. Hemispheres with a carbon dioxide reactivity less than or equal to 18% demonstrated a significant increase in prevalence (P =.007) and volume (P =.003) of internal border zone infarcts compared with hemispheres with a carbon dioxide reactivity greater than or equal to 19%. No association between carbon dioxide reactivity and any other type of ischemic lesion was found. CONCLUSION: In patients with an ICA occlusion, only internal border zone infarcts demonstrate a significant association with diminished cerebral hemodynamics.

Hemodynamic and metabolic changes in transient ischemic attack patients: a magnetic resonance angiography and (1)H-magnetic resonance spectroscopy study performed within 3 days of onset of a transient ischemic attack.

BACKGROUND AND PURPOSE: We investigated whether patients with transient ischemic attack (TIA) have systemic low flow to the brain or an abnormal intracranial flow distribution caused by an abnormal anatomy of the circle of Willis. Furthermore, we investigated whether metabolic changes were present in the brain. METHODS: Forty-four patients with clinically diagnosed TIA were prospectively included in our study. Clinical and neurological data were compiled. MR imaging; quantitative flow measurements of the internal carotid, middle cerebral, and basilar arteries; MR angiography of the circle of Willis; and (1)H-MR spectroscopy were performed in all patients within 3 days of onset of symptoms. RESULTS: Compared with control subjects, TIA patients did not have altered flow volume in any of the arteries and had normal flow distribution through the circle of Willis. In TIA patients, the N-acetylaspartate (NAA)/choline ratio in noninfarcted regions was significantly decreased in the symptomatic hemisphere (1.73+/-0.16) compared with the asymptomatic hemisphere (1.84+/-0.19, P<0.05) and control subjects (1.90+/-0.17, P<0.001). In the symptomatic hemisphere, the lactate/NAA ratio was significantly increased (0.04+/-0.08) compared with control subjects (0.00+/-0.01, P<0.05). Patients with a history of prior TIA had a significantly decreased NAA/choline ratio in both the symptomatic (P<0.05) and asymptomatic (P<0.05) hemispheres compared with TIA patients without a prior TIA. CONCLUSIONS: TIA patients have neurological deficits that are transient; however, metabolic damage to the brain is present up to 3 days after the onset of the symptoms. These metabolic changes are not restricted to the symptomatic hemisphere or to areas close to ischemic lesions.