Clinical Safety of Gadobutrol: Review of Over 25 Years of Use Exceeding 100 Million Administrations.

BACKGROUND: The macrocyclic gadolinium-based contrast agent gadobutrol was introduced to the market in February 1998. Over the last 25 years, gadobutrol has been administered more than 100 million times worldwide providing a wealth of data related to safety. OBJECTIVE: The aim of this study was to perform a thorough review and status update on gadobutrol's safety. MATERIALS AND METHODS: Safety data from the clinical phase II-IV program and postmarketing surveillance were descriptively analyzed from February 1998 until December 31, 2022. Literature on special at-risk populations and specific safety aspects was critically summarized. RESULTS: Forty-five clinical phase II-IV studies recruited 7856 patients receiving gadobutrol. Drug-related adverse events (AEs) were reported in 3.4% and serious AEs in <0.1% of patients. Nausea (0.7%) and dysgeusia (0.4%) were the most reported AEs. All other drug-related AEs occurred ≤0.3%. After more than 100 million gadobutrol administrations, overall adverse drug reactions (ADRs) from postmarketing surveillance (including clinical trials) were rare with an overall reporting rate of 0.0356%, hypersensitivity reactions (0.0147%), nausea (0.0032%), vomiting (0.0025%), and dyspnea (0.0010%). All other ADRs were <0.001%. No trend for higher rates of AEs was found in patients with reduced renal or liver function. Seven clinical studies reported safety findings in 7292 children ≤18 years, thereof 112 newborns/toddlers younger than 2 years. Overall, 61 ADRs (0.84%) were reported, including 3 serious ones. Adverse events in patients ≥65 years of age ("elderly") were significantly less frequent than in younger patients. A total of 4 reports diagnostic of or consistent with nephrogenic systemic fibrosis have been received. No causal relationship has been established between clinical signs and symptoms and the presence of small amounts of gadolinium in the body in patients with normal renal function after use of gadobutrol. CONCLUSIONS: More than 100 million administrations worldwide have shown gadobutrol's well-established benefit-risk profile in any approved indication and populations.

Clinical Efficacy of Gadobutrol: Review of Over 25 Years of Use Exceeding 100 Million Administrations.

BACKGROUND: Gadobutrol has been administered more than 100 million times worldwide, since February 1998, that is, over the last 25 years. Numerous clinical studies in a broad range of indications document the long-term experience with gadobutrol. OBJECTIVE: The aim of this study was to provide a literature-based overview on gadobutrol's efficacy in 9 approved indications and use in children. MATERIALS AND METHODS: Efficacy results in patients of all age groups including sensitivity, specificity, accuracy, and positive/negative predictive values were identified by a systematic literature search on Embase until December 31, 2022. Nine approved indications were considered: central nervous system (CNS), magnetic resonance angiography (MRA), breast, heart, prostate, kidney, liver, musculoskeletal, whole body, and various indications in children. RESULTS: Sixty-five publications (10 phase III, 2 phase IV, 53 investigator-initiated studies) reported diagnostic efficacy results obtained from 7806 patients including 271 children, at 369 centers worldwide. Indication-specific sensitivity ranges were 59%-98% (CNS), 53%-100% (MRA), 80%-100% (breast), 64%-90% (heart), 64%-96% (prostate), 71-85 (kidney), 79%-100% (liver), 53%-98% (musculoskeletal), and 78%-100% (children). Indication-specific specificity ranges were 75%-100% (CNS), 64%-99% (MRA), 58%-98% (breast), and 47%-100% (heart). CONCLUSIONS: The evaluated body of evidence, consisting of 65 studies with 7806 patients, including 271 children and 7535 adults, showed that gadobutrol is an efficacious magnetic resonance imaging contrast agent for all age groups in various approved indications throughout the whole body.

Iopromide for Contrast-Enhanced Mammography: A Systemic Review and Meta-Analysis of Pertinent Literature.

Background: Contrast-enhanced mammography (CEM) is an emerging breast imaging modality. Clinical data is scarce. Objectives: To summarize clinical evidence on the use of iopromide in CEM for the detection or by systematically analyzing the available literature on efficacy and safety. Design: Systematic review and meta-analysis. Data sources and methods: Iopromide-specific publications reporting its use in CEM were identified by a systematic search within Bayer's Product Literature Information (PLI) database and by levering a recent review publication. The literature search in PLI was performed up to January 2023. The confirmatory-supporting review publication was based on a MEDLINE/EMBASE + full text search for publications issued between September 2003 and January 2019. Relevant literature was selected based on pre-defined criteria by 2 reviewers. The comparison of CEM vs traditional mammography (XRM) was performed on published results of sensitivity and specificity. Differences in diagnostic parameters were assessed within a meta-analysis. Results: Literature search: A total of 31 studies were identified reporting data on 5194 patients. Thereof, 19 studies on efficacy and 3 studies on safety. Efficacy: in 11 studies comparing iopromide CEM vs XRM, sensitivity was up to 43% higher (range 1%-43%) for CEM. Differences in specificity were found to be in a range of -4% to 46% for CEM compared with XRM. The overall gain in sensitivity for CEM vs XRM was 7% (95% CI [4%, 11%]) with no statistically significant loss in specificity in any study assessed. In most studies, accuracy, positive predictive value, and negative predictive value were found to be in favor of CEM. In 2 studies comparing CEM with breast magnetic resonance imaging (bMRI), both imaging modalities performed either equally well or CEM tended to show better results with respect to sensitivity and specificity. Safety: eight cases of iopromide-related adverse drug reactions were reported in 1022 patients (0.8%). Conclusions: Pertinent literature provides evidence for clinical utility of iopromide in CEM for the detection or confirmation of breast cancer. The overall gain in sensitivity for iopromide CEM vs XRM was 7% with no statistically significant loss in specificity.

Sensitivity of Contrast-Enhanced Breast MRI vs X-ray Mammography Based on Cancer Histology, Tumor Grading, Receptor Status, and Molecular Subtype: A Supplemental Analysis of 2 Large Phase III Studies.

Background: The impact of certain tumor parameters on the sensitivity of imaging tools is unknown. The purpose was to study the impact of breast cancer histology, tumor grading, single receptor status, and molecular subtype on the sensitivity of contrast-enhanced breast magnetic resonance imaging (CE-BMRI) vs X-ray mammography (XRM) to detect breast cancer. Materials and Methods: We ran a supplemental analysis of 2 global Phase III studies which recruited patients with histologically proven breast cancers. The sensitivity of CE-BMRI vs XRM to detect cancer lesions with different histologies, tumor grading, single receptor status, and molecular subtype was compared. Six blinded readers for each study evaluated the images. Results were summarized as the "Mean Reader." For each reader, sensitivity was defined as the proportion of detected lesions vs the total number of lesions identified by the standard of reference. Two-sided 95% confidence intervals were calculated for within-group proportions, and for the difference between CE-BMRI and XRM, using a normal approximation to the binomial distribution. Results: In 778 patients, 1273 cancer lesions were detected. A total of 435 patients had 1 lesion, 254 had 2 lesions, and 77 had 3 or more lesions. The sensitivity of CE-BMRI was significantly higher compared with XRM irrespective of the histology. The largest difference was seen for invasive lobular carcinoma (22.3%) and ductal carcinoma in situ (19%). Across all 3 tumor grades, the sensitivity advantage of CE-BMRI over XRM ranged from 15.7% to 18.5%. Contrast-enhanced breast magnetic resonance imaging showed higher sensitivity compared with XRM irrespective of single receptor expressions (15.3%-19.4%). The sensitivities for both imaging methods were numerically higher for the more aggressive ER- (estrogen receptor), PR- (progesterone receptor), and HER2+ (human epidermal growth factor receptor 2) tumors. Irrespective of molecular subtype, sensitivity of CE-BMRI was 14.8% to 18.9% higher compared with XRM. Conclusions: Contrast-enhanced breast magnetic resonance imaging showed significantly higher sensitivity compared with XRM independent of tumor histology, tumor grading, single receptor status, and molecular subtype.Trial Registration: ClinicalTrials.gov: NCT01067976 and NCT01104584.

Immunohistochemical assessment of PD-L1 expression using three different monoclonal antibodies in triple negative breast cancer patients.

BACKGROUND: PD-L1 receptor expression in breast cancer tissue can be assessed with different anti-human PD-L1 monoclonal antibodies. The performance of three specific monoclonal antibodies in a head-to-head comparison is unknown. In addition, a potential correlation of PD-L1 expression and clinico-pathological parameters has not been investigated. METHODS: This was a retrospective study on tissue samples of patients with histologically confirmed triple negative breast cancer (TNBC). PD-L1 receptors were immune histochemically stained with three anti-human PD-L1 monoclonal antibodies: 22C3 and 28-8 for staining of tumor cell membranes (TC) and cytoplasm (Cyt), SP142 for immune cell staining (IC). Three different tissue samples of each patient were evaluated separately by two observers in a blinded fashion. The percentage of PD-L1 positive tumor cells in relation to the total number of tumor cells was determined. For antibodies 22C3 and 28-8 PD-L1 staining of 0 to < 1% of tumor cells was rated "negative", 1-50% was rated "positive" and > 50% was rated "strong positive". Cyt staining was defined as "negative" when no signal was observed and as "positive", when any positive signal was observed. For IC staining with SP142 all samples with PD-L1 expression ≥ 1% were rated as "positive". Finally, the relationship between PD-L1 expression and clinico-pathological parameters was analyzed. RESULTS: Tissue samples from 59 of 60 enrolled patients could be analyzed. Mean age was 55 years. Both the monoclonal antibodies 22C3 and 28-8 had similar properties, and were positive for both TC in 13 patients (22%) and for Cyt staining in 24 patients (40.7%). IC staining with antibody SP142 was positive in 24 patients (40.7%), who were also positive for Cyt staining. The differences between TC and Cyt staining and TC and IC staining were significant (p = 0.001). Cases with positive TC staining showed higher Ki67 expression compared to those with negative staining, 40 vs 30%, respectively (p = 0.05). None of the other clinico-pathological parameters showed any correlation with PDL1 expression. CONCLUSIONS: Antibodies 22C3 and 28-8 can be used interchangeably for PD-L1 determination in tumor cells of TNBC patients. Results for Cyt staining with 22C3 or 28-8 and IC staining with SP142 were identical. In our study PD-L1 expression correlates with Ki67 expression but not with OS or DFS.

Risk of Hypersensitivity Reactions to Iopromide in Children and Elderly: An Analysis of 132,850 Patients From 4 Observational Studies and Pharmacovigilance Covering >288 Million Administrations.

PURPOSE: The aim of this study was to analyze the risk of hypersensitivity reactions (HSRs) to iopromide in children and elderly patients in comparison to adults. MATERIALS AND METHODS: Four observational studies were pooled and analyzed (analysis I). In addition, spontaneous reports from 1985 to 2020 from the pharmacovigilance database were evaluated (analysis II). All patients received iopromide for angiographic procedures or contrast-enhanced computed tomography in various indications. In analysis I, a nested case-control analysis, including a multivariable logistic regression model, based on pooled observational study data, was performed. Cases were defined as patients with a typical and unequivocal HSR; controls were patients without any recorded reaction. In analysis II, all spontaneous reports on HSRs after iopromide administration recorded in the pharmacovigilance database were descriptively analyzed. Exposure estimates on the size of the exposed age groups were derived from sales data and data from market research. The primary target variable was the risk of HSR to iopromide in children (<18 years) and elderly patients (≥65 years) compared with adults (≥18 to <65 years). RESULTS: In analysis I, a total of 132,850 patients were included (2978 children, 43,209 elderly, and 86,663 adults). Hypersensitivity reactions were significantly less frequent in children (0.47%) and elderly (0.38%) compared with adults (0.74%). The adjusted odds ratio (vs adults) for children was 0.58 (95% confidence interval, 0.34-0.98; P < 0.043), and that for the elderly was 0.51 (95% confidence interval, 0.43-0.61; P < 0.001), indicating a lower risk for both subpopulations as compared with adults. In analysis II, of the overall >288 million iopromide administrations, 5.87, 114.18, and 167.97 million administrations were administered to children, elderly, and adults, respectively. The reporting rate for HSRs in children (0.0114%) and elderly (0.0071%) was significantly lower as compared with adults (0.0143%) (P < 0.0001). CONCLUSIONS: Hypersensitivity reactions to iopromide were significantly less frequent in children and elderly compared with adults.

Clinical Efficacy of Reduced-Dose Gadobutrol Versus Standard-Dose Gadoterate for Contrast-Enhanced MRI of the CNS: An International Multicenter Prospective Crossover Trial (LEADER-75).

BACKGROUND. Gadobutrol and gadoterate are widely used macrocyclic gadolinium-based contrast agents. Given gadobutrol's higher T1 relaxivity, a reduced gadobutrol dose should achieve essentially equivalent diagnostic efficacy as a standard dose of gadoterate. OBJECTIVE. The purpose of our study was to show efficacy of a 25% reduced dose of gadobutrol is noninferior to 100% standard dose of gadoterate for contrast-enhanced MRI of the CNS. METHODS. In this international prospective multicenter open-label crossover trial (LEADER-75 [Lower Administered Dose With Higher Relaxivity: Gadovist vs Dotarem]), adult patients with known or suspected CNS pathology underwent contrast-enhanced brain MRI with standard-dose gadoterate (0.1 mmol/kg); if an enhancing lesion was identified, a second MRI with reduced-dose gadobutrol (0.075 mmol/kg) was performed within 15 days of the first MRI. Three radiologists independently reviewed images to score three primary efficacy measures: subjective lesion enhancement, lesion border delineation, lesion internal morphology. A noninferiority analysis used readers' mean scores of the primary efficacy measures. Noninferiority of reduced-dose gadobutrol to standard-dose gadoterate for primary efficacy measures was defined as the difference in score between reduced-dose gadobutrol images and unenhanced images achieving at least 80% of the difference in score between standard-dose gadoterate images and unenhanced images. A post hoc analysis was performed to directly compare contrast-enhanced images for equivalence. Secondary efficacy variables included the number of lesions detected, reader confidence, diagnostic performance for malignancy, and reader preference in side-by-side comparison. RESULTS. The efficacy analysis included 141 patients (78 men, 63 women; mean age, 58.5 ± 13.5 [SD] years). Improvement of reduced-dose gadobutrol over unenhanced images was noninferior to improvement of standard-dose gadoterate over unenhanced images using a 20% noninferiority margin for all three primary efficacy measures using mean readings (p ≤ .025). In the post hoc analysis, the mean reading for the three primary efficacy measures differed by less than 1% between reduced-dose gadobutrol and standard-dose gadoterate, supporting equivalence of all measures using a narrow ± 5% margin (p ≤ .025). The total number of lesions detected by mean reading was 301 for reduced-dose gadobutrol versus 291 for standard-dose gadoterate. Mean reader confidence was 3.3 ± 0.6 for reduced-dose gadobutrol versus 3.3 ± 0.6 for standard-dose gadoterate. Sensitivity (58.7%), specificity (91.8%), and accuracy (70.2%) for malignancy from majority reading were identical for reduced-dose gadobutrol and standard-dose gadoterate. Reader preference was not different (95% CI, -0.10 to 0.11). CONCLUSION. A 25% reduced dose of gadobutrol is noninferior to standard-dose gadoterate for contrast-enhanced brain MRI. CLINICAL IMPACT. Use of reduced-dose gadobutrol should be considered for brain MRI, particularly in patients undergoing multiple contrast-enhanced examinations. TRIAL REGISTRATION. ClinicalTrials.gov NCT03602339; EU Clinical Trials Register EudraCT 2018-00690-78.

Impact of concentration and dilution of three macrocyclic gadolinium-based contrast agents on MRI signal intensity at 1.5T and 3T and different pulse sequences: results of a phantom study in human plasma.

BACKGROUND: Many factors influence the increase in signal intensity (SI) provided by magnetic resonance imaging (MRI) contrast media. PURPOSE: To assess the impact of different gadolinium concentrations and dilutions of three macrocyclic gadolinium-based contrast agents (GBCA) on SI. MATERIAL AND METHODS: This phantom study investigated gadobutrol, gadoteridol, and gadoterate in human plasma of a healthy donor pool at 37 °C. Different molar concentrations served to mimic conditions typically relevant for steady-state imaging; different dilutions served to mimic influence on first-pass bolus imaging. For SI measurement at 1.5T and 3T, we used two Magnetom Scanners (Siemens), applying the T1-weighted sequences Flash 2D/3D and VIBE. Regions of interest were placed on the central slice of the test vials. RESULTS: In the concentration series, gadobutrol showed the highest SI of all three GBCAs up to 2 mM, followed by gadoteridol and gadoterate. No major differences were seen between 1.5T and 3T. In the dilution series, gadobutrol showed the highest SI of all three GBCAs up to 10 mL/L. The highest effect was recorded with Flash 3D and VIBE at 3T. CONCLUSION: SIs measured in phantoms using three macrocyclic GBCAs strongly depend on their relaxivity and on the local concentration. The latter can be influenced-when comparing dilutions-by their initial concentration in their formulation. Furthermore, the pulse sequences and the chosen parameters have essential influence. At steady-state concentrations (≤2 mM) and first-pass bolus dilutions (up to 10 ml/L), gadobutrol showed highest SIs, followed by gadoterate and gadoteridol.

Diagnostic efficacy of contrast-enhanced breast MRI versus X-ray mammography in women with different degrees of breast density.

BACKGROUND: Detection of breast cancer in women with high breast densities is a clinical challenge. PURPOSE: To study the influence of different degrees of breast density on the sensitivity of contrast-enhanced breast magnetic resonance imaging (CE-BMRI) versus X-ray mammography (XRM). MATERIAL AND METHODS: We performed an additional analysis of two large Phase III clinical trials (G1; G2) which included women with histologically proven breast cancers, called "index cancers." Additional cancers were detected during image reading. We compared the sensitivity of CE-BMRI and XRM in women with different breast densities (ACR A→D; Version 5). For each study, six blinded readers evaluated the images. Results are given as the "Median Reader." RESULTS: A total of 774 patients were included, 169 had additional cancers. While sensitivity of CE-BMRI for detecting all index cancers was independent of breast density (ACR A→D) (G1: 83%→83%; G2: 91%→91%) the sensitivity of XRM declined (ACR A→D) (G1: 79%→62%; G2: 82%→64%). Thus, the sensitivity difference between both imaging modalities in ACR A breasts of 3% (G1) and 9% (G2) increased to 21% (G1) and 26% (G2) in ACR D breasts. Sensitivity of CE-BMRI for detecting at least one additional cancer increased with increasing breast density (ACR A→D) (G1: 50%→73%, G2: 57%→81%). XRM's sensitivity decreased (G1: 34%→20%) or remained stable (G2: 24%→25%). CONCLUSION: CE-BMRI showed significantly higher sensitivity compared to XRM.

Is vimentin a potential prognostic factor for patients with triple-negative breast cancer?

OBJECTIVE: To evaluate the prognostic potential of vimentin, p53, EGFR, CK5/6, CK 14, and CK 17 in patients with triple-negative breast cancer (TNBC). MATERIAL AND METHODS: Tumor specimens of 60 patients with histologically confirmed TNBC were retrospectively analyzed. Formalin-fixed paraffin-embedded blocks of the tumor tissue were used to prepare tissue microarrays (TMAs). After immune-histochemical staining, protein expression of vimentin, p53, EGFR, CK5/6, CK 14, and CK 17 was determined and the immunoreactive score (IRS) was calculated. The protein expression was correlated to overall (OS) and disease-free survival (DFS). RESULTS: Ninety percent of patients suffered from an invasive ductal carcinoma T1 or T2, 66.7% were N0, and 70% had a G3 tumor with Ki67 of > 14%. Vimentin expression was found in 28/60 patients (46.7%), p53 expression in 30/60 patients (50%), and EGFR expression in 3/60 patients (5%). CK5/6, CK14, and CK17 expression was found in 60.0%, 63.3%, and 66.7%, respectively. Vimentin expression vs no expression was associated with significantly higher mean Ki67 values (52.5% vs. 31.1%; p = 0.0013) and significantly higher p53 expression (67.9% vs. 34.4%; p = 0.0097). No significant association between vimentin expression and OS (p = 0.7710) or DFS (p = 0.5558) was found during a mean follow-up of 92 months. CONCLUSION: None of the six proteins proved to be suitable prognostic factors for OS and DSF in patients with TNBC.

Impact of CT Injector Technology and Contrast Media Viscosity on Vascular Enhancement: Evaluation in a Circulation Phantom.

OBJECTIVE: To assess the impact of piston-based vs peristaltic injection system technology and contrast media viscosity on achievable iodine delivery rates (IDRs) and vascular enhancement in a pre-clinical study. METHODS: Four injectors were tested: MEDRAD® Centargo, MEDRAD® Stellant, CT Exprès®, and CT motion™ using five contrast media [iopromide (300 and 370 mgI ml-1), iodixanol 320 mgI ml-1, iohexol 350 mgI ml-1, iomeprol 400 mgI ml-1]. Three experiments were performed evaluating achievable IDR and corresponding enhancement in a circulation phantom. RESULTS: Experiment I: Centargo provided the highest achievable IDRs with all tested contrast media (p < 0.05). Iopromide 370 yielded the highest IDR with an 18G catheter (3.15 gI/s); iopromide 300 yielded the highest IDR with 20G (2.70 gI/s) and 22G (1.65 gI/s) catheters (p < 0.05).Experiment II: with higher achievable IDRs, piston-based injectors provided significantly higher peak vascular enhancement (up to 48% increase) than the peristaltic injectors with programmed IDRs from 1.8 to 2.4 gI/s (p < 0.05).Experiment III: with programmed IDRs (e.g. 1.5 gI/s) achievable by all injection systems, Centargo, with sharper measured bolus shape, provided significant increases in enhancement of 34-73 HU in the pulmonary artery with iopromide 370 (p < 0.05). CONCLUSION: The tested piston-based injection systems combined with low viscosity contrast media provide higher achievable IDRs and higher peak vascular enhancement than the tested peristaltic-based injectors. With equivalent IDRs, Centargo provides higher peak vascular enhancement due to improved bolus shape. ADVANCES IN KNOWLEDGE: This paper introduces a new parameter to compare expected performance among contrast media: the concentration/viscosity ratio. Additionally, it demonstrates previously unexplored impacts of bolus shape on vascular enhancement.

Comparison of 2 CT Contrast Media Injection Systems: Visual Air Identification and Injector Face Cleaning.

PURPOSE: To compare the MEDRAD Stellant and MEDRAD Stellant FLEX computed tomography contrast media injection systems in terms of radiologic technologists' ability to visually identify air in the syringes at various distances and under different lighting conditions, as well as the ease of cleaning contrast media spills on the injector faces. METHODS: Ten experienced radiologic technologists performed 104 tests (52 per injector) in normal light and in ambient light conditions. The tests were randomized for the radiologic technologists' distance from the injector at 2 ft (61 cm), 8 ft (244 cm), and 16 ft (488 cm). In addition, the authors tested the cleaning efficiency of the Stellant injector face with raised buttons and the Stellant FLEX injector face with buttons on a flush surface by applying a mixture of contrast media and invisible ultraviolet ink. Radiologic technologists followed 2 cleaning protocols: a quick clean (5 seconds) and a full clean (1 minute). Residual contrast mixture was measured. RESULTS: The Stellant FLEX injector had an overall higher rate of correct air identification than did the Stellant injector, 97.5% vs 86.9%, respectively (P < .001), with improvement seen at greater distances. The rates for the Stellant FLEX injector remained stable for all distances (99.4%-93.9%; P < .003). A similar result was seen with ambient lighting: The visibility of air in the Stellant FLEX injector remained stable (P < .001). During cleaning, the Stellant FLEX injector required less time to reach a greater level of cleanliness and showed less contrast mixture residue, especially after the quick clean procedure (16% and 59%, respectively; P < .001). DISCUSSION: Injector manufacturers provide various technologies to assist radiologic technologists in visualizing the presence of air in a syringe. The Stellant injector features clear syringes with FluiDots as an air identification technology. The Stellant FLEX injector incorporates an added feature called Beacon technology. This study's results are highly clinically relevant because unintentional iatrogenic air injection occurs in clinical practice and can, in rare cases, severely harm patients. CONCLUSION: Radiologic technologists showed an improved ability to identify air in the syringes in the Stellant FLEX system. In addition, radiologic technologists were confident about their identification, specifically at greater distances and in ambient lighting conditions. The Stellant FLEX injector face also enabled quicker and more efficient cleaning.

Risk of Hypersensitivity Reactions to Iopromide After Intra-Arterial Versus Intravenous Administration: A Nested Case-Control Analysis of 133,331 Patients.

OBJECTIVE: The aim of this study was to compare the risk of hypersensitivity reactions to iopromide after intra-arterial (IA) administration and intravenous (IV) administration. MATERIALS AND METHODS: Four observational studies were pooled. Almost half of the study population (48.1%) was from Europe, and one quarter each from China (27.6%) and other Asia countries (24.1%). All patients received iopromide either intra-arterially or intravenously for angiographic procedures (mostly cardio-angiography) or contrast-enhanced computed tomography. A nested case-control analysis, including a multivariable logistic regression model, was performed. Cases were defined by patients with a typical and unequivocal hypersensitivity (assumed non-IgE-mediated) reaction; controls were patients without any recorded reaction. The primary target variable is the odds ratio of having a hypersensitivity reaction after IA versus IV administration. RESULTS: A total of 133,331 patients met the inclusion criteria, 105,460 and 27,871 patients received iopromide IV or IA, respectively. Hypersensitivity reactions were recorded for 822 patients, and 132,509 patients served as controls.Major risk factors for hypersensitivity reactions were method of injection (IV vs IA), age (18 to <50 years vs ≥65 years), history of allergy or previous contrast media reaction (all P < 0.001), and asthma (P = 0.005).A total of 766 patients (0.7%) and 56 patients (0.2%) were recorded with hypersensitivity reactions after IV or IA administration, respectively (P < 0.0001).Adjusted odds ratio (IA vs IV) was 0.23 (95% confidence interval, 0.16-0.32) for all countries together: for China only, 0.22 (0.11-0.44); for all countries without China, 0.36 (0.25-0.53).Most frequent reactions were erythema/urticaria/rash, pruritus, and cough/sneezing. CONCLUSIONS: Hypersensitivity reactions to iopromide were significantly less frequently recorded after IA administrations. This could be related to the delayed and diluted arrival of iopromide to the lungs.

Impact of body mass index, smoking habit, alcohol consumption, physical activity and parity on disease course of women with triple-negative breast cancer.

OBJECTIVE: To evaluate the potential impact of body mass index (BMI), smoking habit, alcohol consumption, physical activity and parity on disease course of women with triple-negative breast cancer (TNBC). MATERIAL AND METHODS: This was a retrospective chart analysis of patients with TNBC. Primary target parameters were overall survival (OS) and disease-free survival (DFS) depending on BMI, smoking habit, alcohol consumption, physical activity and parity. Results were descriptively evaluated and plotted as Kaplan-Meier curves. The null hypothesis was tested using the non-parametric log-rank test. All patients were treated at the University Medical School of Saarland, Dept of Gynecology, Obstetrics and Reproductive Medicine. RESULTS: A total of 197 patients were analyzed. More than 50% of women were 40-60 years old (mean 57 years) and had a normal BMI. More than 88% of patients had either a T1 or T2 tumor, 64% were N0 and 66.5% had a G3 cancer. Thirty-four of 84 patients (40.38%) on neo-adjuvant chemotherapy reached a pathology-confirmed complete remission. During the follow-up (median 41.43 months), 34 (17.3%) patients had recurrent disease and 51 (25.9%) suffered from metastases. A total of 51 (25.9%) finally deceased. OS and DFS were not significantly impacted by BMI (OS: p = 0.4720; DFS: p = 0.2272), smoking habit (p = 0.9892; p = 0.6040), alcohol consumption (p = 0.6515; p = 0.7460), physical activity (p = 0.3320; p = 0.5991) or parity (p = 0.5929; 0.1417). CONCLUSION: BMI, smoking habit, alcohol consumption, physical activity and parity had no impact on OS or DFS in women with TNBC.

Comparison of the Relaxivities of Macrocyclic Gadolinium-Based Contrast Agents in Human Plasma at 1.5, 3, and 7 T, and Blood at 3 T.

PURPOSE: The relaxivities of 3 macrocyclic gadolinium-based contrast agents (GBCAs) were determined in human plasma and blood under standardized and clinically relevant laboratory conditions. METHODS: The T1 relaxivity, r1, was determined in human plasma at 1.5, 3, and 7 T, and in human blood at 3 T at 37°C in phantoms containing 4 different concentrations of the macrocyclic GBCAs gadobutrol, gadoteridol, and gadoterate. An inversion recovery turbo spin echo sequence was used to generate images with several inversion times. The T1-times were obtained by fitting the signal intensities to the signal equation. r1 was obtained by a 1/y-weighted regression of the T1-rates over the concentration of the GBCAs. RESULTS: For gadobutrol, the obtained r1 [L/(mmol·s)] in human plasma at 1.5 T, 3 T, and 7 T, and in human blood at 3 T was 4.78 ± 0.12, 4.97 ± 0.59, 3.83 ± 0.24, and 3.47 ± 0.16. For gadoteridol, r1 was 3.80 ± 0.10, 3.28 ± 0.09, 3.21 ± 0.07, and 2.61 ± 0.16, and for gadoterate, 3.32 ± 0.13, 3.00 ± 0.13, 2.84 ± 0.09, and 2.72 ± 0.17. CONCLUSIONS: The relaxivity of gadobutrol is significantly higher than that of gadoteridol and gadoterate at all magnetic field strengths and in plasma as well as in blood, whereas that of gadoteridol was higher than gadoterate only in plasma at 1.5 and 7 T. This is in accordance with results from 3 previous studies obtained in different media.

Muscle mass loss in patients with metastatic breast cancer.

PURPOSE: To assess the change of body mass index (BMI), muscle mass, visceral and subcutaneous fat in patients with metastatic breast cancer. METHODS: In this retrospective chart analysis, patients with metastatic breast cancer as initial diagnosis between 2012 and 2016 were analyzed. Patients had received either chemotherapy (CTH) or endocrine therapy (ETH) according to the German S3 Guideline. BMI was calculated from the patients' weight and height. Change of muscle mass, visceral and subcutaneous fat was determined by comparing the surface area of these tissues on transverse CT images at the level of the third lumbar vertebrae (L3) at baseline and during treatment. RESULTS: A total of 45 patients were included in the study, 29 on CTH and 16 on ETH. BMI, visceral and subcutaneous fat remained stable over time for both treatment groups. When taking both treatment groups together, muscle mass decreased significantly by 5.0 ± 2.5 cm2 per year (p < 0.05). CONCLUSION: In patients with metastatic breast cancer, a slight reduction of muscle mass was observed, independent of therapy regimes.

Piston-Based vs Peristaltic Pump-Based CT Injector Systems.

PURPOSE: To compare the fluid delivery performance of 2 different technologies for administration of iodinated contrast media in computed tomography (CT). METHODS: The maximum achievable flow rate and the steady-state flow rate variance of a piston-based contrast media injector system (Stellant MP, MEDRAD) was compared with peristaltic pump-based injector systems (CT motion, Ulrich Medical; CT Exprès, Bracco). The contrast media iopromide (Ultravist) and iopamidol (Isovue) were used at 2 concentrations each (300 and 370 mg I/mL) and 3 catheter sizes (18, 20, and 22 G) to test the injector performance. RESULTS: Average maximum achievable flow rates for room temperature iopromide (370 mg I/mL) using a 20 G catheter were 7.6, 7.1, and 4.8 mL per second for the Stellant MP injector, CT motion injector, and CT Exprès injector, respectively. The Stellant MP injector achieved significantly higher flow rates compared to the CT Exprès injector for all catheter sizes tested (P<.001). Higher flow rates also were observed for the Stellant MP injector compared to the CT motion injector, with 20 G and 22 G catheters (P<.001). The Stellant MP injector featured a constant steady-state flow rate (variance<0.04 mL/s), whereas the other systems injected in a pulsatile fashion, with significantly greater variance (P<.001). DISCUSSION: To the authors' knowledge, this is the first reported laboratory study providing preliminary evidence of differences between the fluid delivery performance of CT injection systems. Additional investigations using a dedicated flow phantom simulating human physiological flow parameters should be conducted, and depending on the results, a clinical study could assess the effect on image quality. CONCLUSION: The piston-based injector demonstrated higher maximum achievable flow rates and more consistent steady-state flow when compared to peristaltic pump-based injectors.

Diagnostic Efficacy and Safety of Gadoxetate Disodium vs Gadobenate Dimeglumine in Patients With Known or Suspected Focal Liver Lesions: Results of a Clinical Phase III Study.

PURPOSE: The aim of this study is to evaluate the diagnostic efficacy and safety of gadoxetate disodium vs gadobenate dimeglumine in patients with known or suspected focal liver lesions. METHODS: This was a prospective, multicenter, double-blind, randomized, inter-individual Phase III study. The primary target-technical efficacy-was already published. Here, secondary efficacy parameters-sensitivity and specificity-and safety in specific patient populations are presented. Patients with suspected or known focal liver lesions scheduled for contrast-enhanced liver magnetic resonance imaging (MRI) were recruited and categorized in 4 a priori specified subgroups: (1) all patients, (2) patients with liver cancer (hepatocellular carcinoma [HCC]), (3) patients with cirrhosis, and (4) patients with HCC + cirrhosis. Dual multi-detector liver computed tomography (CT) served as standard of reference. RESULTS: A total of 295 patients were included. While the overall increase in sensitivity across all 4 patient groups was comparable for gadoxetate disodium (increase from pre- to post-contrast ranging from 6.2% to 9.9%) and gadobenate dimeglumine (ranging from -2.9% to 10.0%), significant differences were seen for some of the subgroups. There was a significantly higher increase in sensitivity for gadoxetate disodium in patients with HCC (7%) and HCC + cirrhosis (12.8%) in comparison with gadobenate dimeglumine. Specificity decreased for both agents: gadoxetate disodium by -2.8% to -6.3% and gadobenate dimeglumine by -3.3% to -8.7%. Gadoxetate showed a significantly lower loss of specificity in all subgroups. Safety was comparable in both groups. CONCLUSIONS: Gadoxetate disodium proved to be an effective liver-specific MRI contrast agent. Some distinct advantages over gadobenate dimeglumine were demonstrated in patients with HCC and patients with HCC + liver cirrhosis for sensitivity and specificity in liver lesion detection.