Pilot study: A simple CAD-based tool to detect breast cancer on MRI of the breast.

PURPOSE: This pilot-study aims to assess, whether quantitatively assessed enhancing breast tissue as a percentage of the entire breast volume can serve as an indicator of breast cancer at breast MRI and whether the contrast-agent employed affects diagnostic efficacy. MATERIALS: This retrospective IRB-approved study, included 39 consecutive patients, that underwent two subsequent breast MRI exams for suspicious findings at conventional imaging with 0.1 mmol/kg gadobenic and gadoteric acid. Two independent readers, blinded to the histopathological outcome, assessed unenhanced and early post-contrast images using computer-assisted software (Brevis, Siemens Healthcare). Diagnostic performance was statistically determined for percentage of ipsilateral voxel volume enhancement and for percentage of contralateral enhancing voxel volume subtracted from ipsilateral enhancing voxel volume after crosstabulation with the dichotomized histological outcome (benign/malignant). RESULTS: Ipsilateral enhancing voxel volume versus histopathological outcome resulted in an AUC of 0.707 and 0.687 for gadobenic acid, reader 1 and 2, respectively and in an AUC of 0.778 and 0.773 for gadoteric acid, reader 1 and 2, respectively. Accounting for background parenchymal enhancement by subtracting contralateral enhancing volume from ipsilateral enhancing voxel volume versus histolopathological outcome resulted in an AUC of 0.793 and 0.843 for gadobenic acid, reader 1 and 2, respectively and in an AUC of 0.692 and 0.662 for gadoteric acid, reader 1 and 2, respectively. Pairwise testing yielded no statistically significant difference both between readers and between contrast agents employed (p > 0.05). CONCLUSION: Our proposed CAD algorithm, which quantitatively assesses enhancing breast tissue as a percentage of the entire breast volume, allows indicating the presence of breast cancer.

Automated analysis of the total choline resonance peak in breast proton magnetic resonance spectroscopy.

The aim of the current study was to compare the performance of fully automated software with human expert interpretation of single-voxel proton magnetic resonance spectroscopy (1H-MRS) spectra in the assessment of breast lesions. Breast magnetic resonance imaging (MRI) (including contrast-enhanced T1-weighted, T2-weighted, and diffusion-weighted imaging) and 1H-MRS images of 74 consecutive patients were acquired on a 3-T positron emission tomography-MRI scanner then automatically imported into and analyzed by SpecTec-ULR 1.1 software (LifeTec Solutions GmbH). All ensuing 117 spectra were additionally independently analyzed and interpreted by two blinded radiologists. Histopathology of at least 24 months of imaging follow-up served as the reference standard. Nonparametric Spearman's correlation coefficients for all measured parameters (signal-to-noise ratio [SNR] and integral of total choline [tCho]), Passing and Bablok regression, and receiver operating characteristic analysis, were calculated to assess test diagnostic performance, as well as to compare automated with manual reading. Based on 117 spectra of 74 patients, the area under the curve for tCho SNR and integrals ranged from 0.768 to 0.814 and from 0.721 to 0.784 to distinguish benign from malignant tissue, respectively. Neither method displayed significant differences between measurements (automated vs. human expert readers, p > 0.05), in line with the results from the univariate Spearman's rank correlation coefficients, as well as the Passing and Bablok regression analysis. It was concluded that this pilot study demonstrates that 1H-MRS data from breast MRI can be automatically exported and interpreted by SpecTec-ULR 1.1 software. The diagnostic performance of this software was not inferior to human expert readers.

Non-Invasive Assessment of Hypoxia and Neovascularization with MRI for Identification of Aggressive Breast Cancer.

The aim of this study was to investigate the potential of magnetic resonance imaging (MRI) for a non-invasive synergistic assessment of tumor microenvironment (TME) hypoxia and induced neovascularization for the identification of aggressive breast cancer. Fifty-three female patients with breast cancer underwent multiparametric breast MRI including quantitative blood-oxygen-level-dependent (qBOLD) imaging for hypoxia and vascular architecture mapping for neovascularization. Quantitative MRI biomarker maps of oxygen extraction fraction (OEF), metabolic rate of oxygen (MRO2), mitochondrial oxygen tension (mitoPO2), microvessel radius (VSI), microvessel density (MVD), and microvessel type indicator (MTI) were calculated. Histopathology was the standard of reference. Histopathological markers (vascular endothelial growth factor receptor 1 (FLT1), podoplanin, hypoxia-inducible factor 1-alpha (HIF-1alpha), carbonic anhydrase 9 (CA IX), vascular endothelial growth factor C (VEGF-C)) were used to confirm imaging biomarker findings. Univariate and multivariate regression analyses were performed to differentiate less aggressive luminal from aggressive non-luminal (HER2-positive, triple negative) malignancies and assess the interplay between hypoxia and neoangiogenesis markers. Aggressive non-luminal cancers (n = 40) presented with significantly higher MRO2 (i.e., oxygen consumption), lower mitoPO2 values (i.e., hypoxia), lower MTI, and higher MVD than less aggressive cancers (n = 13). Data suggest that a model derived from OEF, mitoPO2, and MVD can predict tumor proliferation rate. This novel MRI approach, which can be easily implemented in routine breast MRI exams, aids in the non-invasive identification of aggressive breast cancer.

Evaluation of 3.0-T MRI Brain Signal after Exposure to Gadoterate Meglumine in Women with High Breast Cancer Risk and Screening Breast MRI.

Background Otherwise healthy women at high risk for breast cancer undergo annual contrast agent-enhanced breast MRI screening examinations, resulting in high cumulative doses of gadolinium-based contrast agents (GBCAs). Whereas the majority of studies showed no T1 signal ratio increase in deep brain nuclei after more than six doses of macrocyclic GBCA, this has not been explored in a healthy study population. Purpose To assess whether women who are administered large cumulative doses of macrocyclic GBCA with breast MRI at high-risk breast cancer screening exhibit T1 alterations in deep brain nuclei. Materials and Methods In this prospective study from November 2017 to March 2018, healthy women who were either exposed (because of high-risk breast cancer screening) or unexposed to only gadoterate meglumine underwent 3.0-T brain MRI with a dedicated head coil, including T1 mapping and magnetization-prepared rapid gradient-echo sequences. T1 times and T1 signal intensities were measured in the dentate nucleus (DN), globus pallidus (GP), crus anterior of capsula interna (CA), and pons. Ratios of DN to pons and GP to CA were calculated, and univariable Pearson correlation coefficients were calculated. Multivariable analysis included partial regression analysis. Results This study evaluated 25 women (mean age, 51 years ± 11 [standard deviation]) who were exposed to a mean GBCA dose of 129 mL (median 112 mL; range, 70-302 mL) and 16 women (mean age, 37 years ± 10) who were never exposed to any GBCA. Infratentorially, no correlation between cumulative GBCA dose and T1 times or signal intensity ratios was detected (P = .66 and .55, respectively). In partial correlation analysis by considering age as a confounder, there was a moderate negative correlation between GP-to-CA ratio and GBCA dose (r = -0.40; P = .01) but not for GP T1 times (r = 0.19; P = .24). Conclusion After administration of relatively large cumulative doses of gadoterate dimeglumine, healthy women at high risk for breast cancer who underwent annual contrast-enhanced breast MRI screening did not exhibit T1 signal increase in deep brain nuclei at 3.0-T MRI. © RSNA, 2019.

Development of a Non-invasive Assessment of Hypoxia and Neovascularization with Magnetic Resonance Imaging in Benign and Malignant Breast Tumors: Initial Results.

PURPOSE: To develop a novel magnetic resonance imaging (MRI) approach for the noninvasive assessment of hypoxia and neovascularization in breast tumors. PROCEDURES: In this IRB-approved prospective study, 20 patients with suspicious breast lesions (BI-RADS 4/5) underwent multiparametric breast MRI including quantitative BOLD (qBOLD) and vascular architecture mapping (VAM). Custom-made in-house MatLab software was used for qBOLD and VAM data postprocessing and calculation of quantitative MRI biomarker maps of oxygen extraction fraction (OEF), metabolic rate of oxygen (MRO2), and mitochondrial oxygen tension (mitoPO2) to measure tissue hypoxia and neovascularization including vascular architecture including microvessel radius (VSI), density (MVD), and type (MTI). Histopathology was used as standard of reference. Appropriate statistics were performed to assess and compare correlations between MRI biomarkers for hypoxia and neovascularization. RESULTS: qBOLD and VAM data with good quality were obtained from all patients with 13 invasive ductal carcinoma (IDC) and 7 benign breast tumors with a lesion diameter of at least 10 mm in all spatial directions. MRI biomarker maps of oxygen metabolism and neovascularization demonstrated intratumoral spatial heterogeneity with a broad range of biomarker values. Bulk tumor neovasculature consisted of draining venous microvasculature with slow flowing blood. High OEF and low mitoPO2 were associated with low MVD and vice versa. The heterogeneous pattern of MRO2 values showed spatial congruence with VSI. IDCs showed significantly higher MRO2 (P = 0.007), lower mitoPO2 (P = 0.021), higher MVD (P = 0.005), and lower (i.e., more pathologic) MTI (P = 0.001) compared with benign breast tumors. These results indicate that IDCs consume more oxygen and are more hypoxic and neovascularized than benign tumors. CONCLUSIONS: We developed a novel MRI approach for the noninvasive assessment of hypoxia and neovascularization in benign and malignant breast tumors that can be easily integrated in a diagnostic MRI protocol and provides insight into intratumoral heterogeneity.

Is breast MRI a helpful additional diagnostic test in suspicious mammographic microcalcifications?

PURPOSE: Microcalcifications are a common finding in mammography and usually require invasive procedures to diagnose or exclude malignancy. As many microcalcifications are due to benign lesions, we wanted to assess whether breast MRI as an additional diagnostic tool may be used to distinguish benign from malignant in this setting. MATERIALS AND METHODS: Eligible for this retrospective, IRB-approved observational study were 858 consecutive patients (mean age 54±11years) undergoing stereotactically-guided biopsies of suspicious mammographic microcalcifications during three year at our institution. Finally included were 152 patients who also underwent breast MRI <8weeks prior to biopsy. In case of malignant or lesions of uncertain malignant potential, subsequent surgery was performed. Benign findings were confirmed by imaging follow-up. BI-RADS category assignments from the original mammography and breast MRI reports were compared to the final diagnosis (benign vs. malignant) to determine diagnostic benchmarks. RESULTS: Histopathology revealed 81 benign (53.3%), 41 DCIS (27%) and 30 (19.7%) invasive cancers. Sensitivity, specificity, positive and negative predictive values for breast MRI were 97.2% (69/71), 39.5% (32/81), 58.5% (69/118) and 94.1% (32/34), respectively. Thus, 32/81 unnecessary biopsies in benign lesions (39.5%) may have been avoided, missing 2/71 malignant lesions (2.8%), both DCIS G2. CONCLUSION: Breast MRI as an additional diagnostic tool can be used to accurately distinguish benign from malignant mammographic microcalcifications and may thus be helpful to reduce unnecessary breast biopsies.

MRI for the assessment of malignancy in BI-RADS 4 mammographic microcalcifications.

PURPOSE: Assess the performance of breast MRI to diagnose breast cancer in BI-RADS 4 microcalcifications detected by mammography. MATERIALS AND METHODS: This retrospective, IRB-approved study included 248 consecutive contrast-enhanced breast MRI (1.5T, protocol in accordance with EUSOBI recommendations) performed to further diagnose BI-RADS 4 microcalcifications detected at mammography during a 3-year period. Standard of reference had to be established by histopathology. Routine consensus reading results by two radiologists were dichotomized as positive or negative and compared with the reference standard (benign vs malignant) to calculate diagnostic parameters. RESULTS: There were 107 malignant and 141 benign microcalcifications. Malignancy rates were 18.3% (23/126 BI-RADS 4a), 41.7% (25/60 BI-RADS 4b) and 95% (59/62 BI-RADS 4c). There were 103 true-positive, 116 true-negative, 25 false-positive, and 4 false-negative (one invasive cancer, three DCIS; 2 BI-RADS 4c, 1 BI-RADS 4b on mammography) breast MRI findings, effecting a sensitivity, specificity, PPV, and NPV of 96.3% (95%-CI 90.7-99.0%), 82.3% (95%-CI 75.0-88.2%), 80.5% (95%-CI 72.5-87.0%) and 96.7% (95%-CI 91.7-99.1%), respectively. CONCLUSION: MRI is an accurate tool to further diagnose BI-RADS 4a and 4b microcalcifications and may be helpful to avoid unnecessary biopsies in BI-RADS 4a and 4b lesions. BI-RADS 4c microcalcifications should be biopsied irrespective of MRI findings.

Automated Semi-Quantitative Analysis of Breast MRI: Potential Imaging Biomarker for the Prediction of Tissue Response to Neoadjuvant Chemotherapy.

BACKGROUND: We aimed to investigate an automated semi-quantitative software as an imaging biomarker for the prediction of tissue response (TR) after completion of neoadjuvant chemotherapy (NAC). METHODS: Breast magnetic resonance imaging (MRI) (1.5T, protocol according to international recommendations) of 67 patients with biopsy-proven invasive breast cancer were examined before and after NAC. After completion of NAC, histopathologic assessments of TR were classified according to the Chevallier grading system (CG1/4: full/non-responder; CG2/C3: partial responder). A commercially available fully automatic software (CADstream) extracted MRI parameters of tumor extension (tumor diameter/volume: TD/TV). Pre- versus post-NAC values were compared (ΔTV and ΔTD). Additionally, the software performed volumetric analyses of vascularization (VAV) after NAC. Accuracy of MRI parameters to predict TR were identified (cross-tabs, ROC, AUC, Kruskal-Wallis). RESULTS: There were 37 (34.3%) CG1, 7 (6.5%) CG2, 53 (49.1%) CG3, and 11 (10.2%) CG4 lesions. The software reached area under the curve levels of 79.5% (CG1/complete response: ΔTD), 68.6% (CG2, CG3/partial response: VAV), and 88.8% to predict TR (CG4/non-response: ΔTV). CONCLUSION: Semi-quantitative automated analysis of breast MRI data enabled the prediction of tissue response to NAC.

MR Imaging for Diagnosis of Malignancy in Mammographic Microcalcifications: A Systematic Review and Meta-Analysis.

Purpose To assess the use of magnetic resonance (MR) imaging for diagnosis of malignancy in lesions that manifest as microcalcifications at mammography. Materials and Methods Two independent readers performed a systematic review of the literature published as of February 1, 2016, by using predefined search terms. All studies in which contrast material-enhanced MR imaging was used for assessment of mammographic microcalcifications that were assigned Breast Imaging Reporting and Data System (BI-RADS) scores of 3-5 were deemed eligible. The standard of reference was established at clinical follow-up examination or histopathologic evaluation. Study design, technical parameters, number of true- and false-positive and true- and false-negative results were extracted to fit a cross-tabulation. Quality Assessment of Diagnostic Accuracy Studies-2 applet was used to probe for bias. Statistical analysis included data pooling, meta-regression, heterogeneity testing, and forest plot construction. Results Twenty studies met the inclusion criteria. These comprised 1843 lesions with a mean prevalence of malignancy of 40.6%. Bivariate analysis revealed pooled sensitivity and specificity of 87% (95% confidence interval [CI]: 81%, 92%) and 81% (95% CI: 75%, 86%) for all lesions, respectively; 95% (95% CI: 91%, 98%) and 61% (95% CI: 52%, 69%) for invasive lesions only, respectively; 57% (95% CI: 59%, 81%) and 32% (95% CI: 15%, 92%) for BI-RADS 3 lesions, respectively; 92% (95% CI: 85%, 96%) and 82% (95% CI: 74%, 88%) for BI-RADS 4 lesions, respectively; and 95% (95% CI: 87%, 99%) and 66% (95% CI: 26%, 92%) for BI-RADS 5 lesions. Diagnostic criteria other than presence of enhancement were inversely associated with sensitivity (P ≤ .013). Conclusion Breast MR imaging is not recommended for diagnosis of malignancy in BI-RADS 3 and 5 mammographic microcalcifications, but can be considered for BI-RADS 4 mammographic microcalcifications. The presence or absence of enhancement is the preferable diagnostic criterion to rule out malignancy in mammographic microcalcifications at breast MR imaging. © RSNA, 2016 Online supplemental material is available for this article.

Correction: MRI Background Parenchymal Enhancement Is Not Associated with Breast Cancer.

[This corrects the article DOI: 10.1371/journal.pone.0158573.].

Diagnostic Performance of Breast Magnetic Resonance Imaging in Non-Calcified Equivocal Breast Findings: Results from a Systematic Review and Meta-Analysis.

OBJECTIVES: To evaluate the performance of MRI for diagnosis of breast cancer in non-calcified equivocal breast findings. MATERIALS AND METHODS: We performed a systematic review and meta-analysis of peer-reviewed studies in PubMed from 01/01/1986 until 06/15/2015. Eligible were studies applying dynamic contrast-enhanced breast MRI as an adjunct to conventional imaging (mammography, ultrasound) to clarify equivocal findings without microcalcifications. Reference standard for MRI findings had to be established by histopathological sampling or imaging follow-up of at least 12 months. Number of true or false positives and negatives and other characteristics were extracted, and possible bias was determined using the QUADAS-2 applet. Statistical analyses included data pooling and heterogeneity testing. RESULTS: Fourteen out of 514 studies comprising 2,316 lesions met our inclusion criteria. Pooled diagnostic parameters were: sensitivity (99%, 95%-CI: 93-100%), specificity (89%, 95%-CI: 85-92%), PPV (56%, 95%-CI: 42-70%) and NPV (100%, 95%-CI: 99-100%). These estimates displayed significant heterogeneity (P<0.001). CONCLUSIONS: Breast MRI demonstrates an excellent diagnostic performance in case of non-calcified equivocal breast findings detected in conventional imaging. However, considering the substantial heterogeneity with regard to prevalence of malignancy, problem solving criteria need to be better defined.

MRI Background Parenchymal Enhancement Is Not Associated with Breast Cancer.

BACKGROUND: Previously, a strong positive association between background parenchymal enhancement (BPE) at magnetic resonance imaging (MRI) and breast cancer was reported in high-risk populations. We sought to determine, whether this was also true for non-high-risk patients. METHODS: 540 consecutive patients underwent breast MRI for assessment of breast findings (BI-RADS 0-5, non-high-risk screening (no familial history of breast cancer, no known genetic mutation, no prior chest irradiation, or previous breast cancer diagnosis)) and subsequent histological work-up. For this IRB-approved study, BPE and fibroglandular tissue FGT were retrospectively assessed by two experienced radiologists according to the BI-RADS lexicon. Pearson correlation coefficients were calculated to explore associations between BPE, FGT, age and final diagnosis of breast cancer. Subsequently, multivariate logistic regression analysis, considering covariate colinearities, was performed, using final diagnosis as the target variable and BPE, FGT and age as covariates. RESULTS: Age showed a moderate negative correlation with FGT (r = -0.43, p<0.001) and a weak negative correlation with BPE (r = -0.28, p<0.001). FGT and BPE correlated moderately (r = 0.35, p<0.001). Final diagnosis of breast cancer displayed very weak negative correlations with FGT (r = -0.09, p = 0.046) and BPE (r = -0.156, p<0.001) and weak positive correlation with age (r = 0.353, p<0.001). On multivariate logistic regression analysis, the only independent covariate for prediction of breast cancer was age (OR 1.032, p<0.001). CONCLUSIONS: Based on our data, neither BPE nor FGT independently correlate with breast cancer risk in non-high-risk patients at MRI. Our model retained only age as an independent risk factor for breast cancer in this setting.

Inflammation Modulates RLIP76/RALBP1 Electrophile-Glutathione Conjugate Transporter and Housekeeping Genes in Human Blood-Brain Barrier Endothelial Cells.

Endothelial cells are often present at inflammation sites. This is the case of endothelial cells of the blood-brain barrier (BBB) of patients afflicted with neurodegenerative disorders such as Alzheimer's, Parkinson's, or multiple sclerosis, as well as in cases of bacterial meningitis, trauma, or tumor-associated ischemia. Inflammation is a known modulator of gene expression through the activation of transcription factors, mostly NF-κB. RLIP76 (a.k.a. RALBP1), an ATP-dependent transporter of electrophile-glutathione conjugates, modulates BBB permeability through the regulation of tight junction function, cell adhesion, and exocytosis. Genes and pathways regulated by RLIP76 are transcriptional targets of tumor necrosis factor alpha (TNF-α) pro-inflammatory molecule, suggesting that RLIP76 may also be an inflammation target. To assess the effects of TNF-α on RLIP76, we faced the problem of choosing reference genes impervious to TNF-α. Since such genes were not known in human BBB endothelial cells, we subjected these to TNF-α, and measured by quantitative RT-PCR the expression of housekeeping genes commonly used as reference genes. We find most to be modulated, and analysis of several inflammation datasets as well as a metaanalysis of more than 5000 human tissue samples encompassing more than 300 cell types and diseases show that no single housekeeping gene may be used as a reference gene. Using three different algorithms, however, we uncovered a reference geneset impervious to TNF-α, and show for the first time that RLIP76 expression is induced by TNF-α and follows the induction kinetics of inflammation markers, suggesting that inflammation can influence RLIP76 expression at the BBB. We also show that MRP1 (a.k.a. ABCC1), another electrophile-glutathione transporter, is not modulated in the same cells and conditions, indicating that RLIP76 regulation by TNF-α is not a general property of glutathione transporters. The reference geneset uncovered herein should aid in future gene expression studies in inflammatory conditions of the BBB.

Gene symbol precision.

Several gene databases, including heavily used ones such as the National Center for Biotechnology Information (NCBI) database, erroneously assign, on occasion, literature references to genes or proteins. These mistakes are mostly due to an overlap in gene aliases, whereby two distinct genes share a pseudonym. This is particularly confusing when the gene products have also biological properties in common, are part of signaling pathways that cross-talk to one another, or are regulated by the same effectors. We present examples spanning several research fields including apoptosis, ubiquitin-dependent degradation, signaling by Notch, Wnt, and small G proteins, transporters of glutathione conjugates of electrophiles, and mitochondrial and ribosomal RNA genes. To solve the problem, we argue in favor of including Entrez gene numbers in papers submitted for publication as unique gene identifiers to allow precise identification of genes and species studied.

Blood-brain barrier cell line PBMEC/C1-2 possesses functionally active P-glycoprotein.

The blood-brain barrier (BBB) maintains the homeostasis between the central nervous system and the blood circulation. One of the main efflux transporter proteins at the BBB is P-glycoprotein (P-gP) also known as ABCB1 or MDR1. Due to the important role of P-gP for the transport barrier function of the BBB, the presence and functionality of P-gP was investigated in porcine cell line PBMEC/C1-2. Presence of P-gP was confirmed on the protein level by western blotting and immunofluorescence microscopy as well as on the mRNA level by qPCR. Functional assessment was accomplished by an established 96-well uptake assay using Rhodamine 123 and Doxorubicin as P-gP substrates and Verapamil as moderate P-gP inhibitor. In this regard, fluorescence microscopy confirmed a significant higher uptake of Rhodamine 123 into PBMEC/C1-2 cells when preincubated with Verapamil. Finally, knock-down of P-gP by antisense oligonucleotides revealed an increase of Rhodamine 123 uptake indicating decreased P-gP functionality. In summary, the presence and functionality of P-gP in the immortalised cell line PBMEC/C1-2 was proven with several techniques and assays. Thus, this cell line could be used for P-gP studies in the context of BBB relevant issues.