Marc Lobbes

Pre-treatment differences and early response monitoring of neoadjuvant chemotherapy in breast cancer patients using magnetic resonance imaging: a systematic review.

ObjectivesTo assess whether magnetic resonance imaging (MRI) can identify pre-treatment differences or monitor early response in breast cancer patients receiving neoadjuvant chemotherapy.MethodsPubMed, Cochrane library, Medline and Embase databases were searched for publications until January 1, 2012. After primary selection, studies were selected based on predefined inclusion/exclusion criteria. Two reviewers assessed study contents using an extraction form.ResultsIn 15 studies, which were mainly underpowered and of heterogeneous study design, 31 different parameters were studied. Most frequently studied parameters were tumour diameter or volume, Ktrans, Kep, Ve, and apparent diffusion coefficient (ADC). Other parameters were analysed in only two or less studies. Tumour diameter, volume, and kinetic parameters did not show any pre-treatment differences between responders and non-responders. In two studies, pre-treatment differences in ADC were observed between study groups. At early response monitoring significant and non-significant changes for all parameters were observed for most of the imaging parameters.ConclusionsEvidence on distinguishing responders and non-responders to neoadjuvant chemotherapy using pre-treatment MRI, as well as using MRI for early response monitoring, is weak and based on underpowered study results and heterogeneous study design. Thus, the value of breast MRI for response evaluation has not yet been established.Key Points• Few well-validated pre-treatment MR parameters exist that identify responders and non-responders.• Eligible studies showed heterogeneous study designs which hampered pooling of data.• Confounders and technical variations of MRI accuracy are not studied adequately.• Value of MRI for response evaluation needs to be established further.

Molecular MRI of early thrombus formation using a bimodal alpha2-antiplasmin-based contrast agent

OBJECTIVES We aimed to investigate whether early thrombus formation can be visualized with in vivo magnetic resonance imaging (MRI) by the use of a novel bimodal alpha(2)-antiplasmin-based contrast agent (CA). BACKGROUND Thrombus formation plays a central role in several vascular diseases. During the early phases of thrombus formation, activated factor XIII (FXIIIa) covalently cross-links alpha(2)-antiplasmin to fibrin, indicating the potential of alpha(2)-antiplasmin-based CAs in the detection of early thrombus formation. METHODS A bimodal CA was synthesized by coupling gadolinium-diethylene triamine pentaacetic acid and rhodamine to an alpha(2)-antiplasmin-based peptide. For the control CA, a glutamine residue essential for cross-linking was replaced by alanine. In vitro-generated thrombi were exposed to both CAs and imaged by MRI and 2-photon laser-scanning microscopy. Immunohistochemistry was performed on human pulmonary thromboemboli sections to determine the presence of alpha(2)-antiplasmin and FXIII in different thrombus remodeling phases. In vivo feasibility of the CA in detecting early thrombus formation specifically was investigated with MRI. RESULTS In vitro-generated thrombi exposed to the alpha(2)-antiplasmin-based CA showed hyperintense magnetic resonance signal intensities at the thrombus edge. No hyperintense signal was observed when we used the alpha(2)-antiplasmin-based CA in the presence of FXIII inhibitor dansylcadaverine nor when we used the control CA. Two-photon laser-scanning microscopy demonstrated that the alpha(2)-antiplasmin-based CA bound to fibrin. Immunohistochemistry demonstrated substantial alpha(2)-antiplasmin staining in fresh compared with lytic and organized thrombi. The administration of CA in vivo within seconds after inducing thrombus formation increased contrast-to-noise ratios (CNRs 2.28 +/- 0.39, n=6) at the site of thrombus formation compared with the control CA (CNRs -0.14 +/- 0.55, p = 0.003, n = 6) and alpha(2)-antiplasmin-based CA administration 24 to 48 h after thrombus formation (CNRs 0.11 +/- 0.23, p = 0.006, n = 6). CONCLUSIONS A bimodal CA was developed, characterized, and validated. Our results showed that this bimodal CA enabled noninvasive in vivo magnetic resonance visualization of early thrombus formation.

Contrast enhanced mammography: Techniques, current results, and potential indications

Contrast enhanced mammography: Techniques, current results, and potential indications M.B.I. Lobbes *, M.L. Smidt , J. Houwers , V.C. Tjan-Heijnen , J.E. Wildberger a Department of Radiology, Maastricht University Medical Center, Maastricht, The Netherlands Department of Surgical Oncology, Maastricht University Medical Center, Maastricht, The Netherlands Department of Medical Oncology, Maastricht University Medical Center, Maastricht, The Netherlands

Atherosclerosis : contrast-enhanced MR imaging of vessel wall in rabbit model-comparison of gadofosveset and gadopentetate dimeglumine

PURPOSE To investigate the potential of gadofosveset for contrast material-enhanced magnetic resonance (MR) imaging of plaque in a rabbit model of atherosclerosis. MATERIALS AND METHODS All experiments were approved by the animal ethics committee. Thirty-one New Zealand White rabbits were included in one of four study groups: animals with atherosclerosis imaged with gadofosveset (n = 10) or gadopentetate dimeglumine (n = 7) and control animals imaged with gadofosveset (n = 7) or gadopentetate dimeglumine (n = 7). Aortic atherosclerosis was induced through endothelial denudation combined with a cholesterol-enriched diet. Control rabbits underwent a sham surgical procedure and received a regular diet. After 8 weeks, pre- and postcontrast T1-weighted MR images of the aortic vessel wall were acquired. Relative signal enhancement was determined with dedicated software. Statistical analysis was performed by using a generalized linear mixed model. Immunohistochemical staining with CD31 and albumin was used to assess microvessel density and the albumin content of the vascular wall. Group differences were analyzed by using a chi(2) test. Gadofosveset spatial distribution and content within the vessel wall were determined with proton-induced x-ray emission (PIXE) analysis. RESULTS Postcontrast signal enhancement was significantly greater for atherosclerotic than for control animals imaged with gadofosveset (P = .022). Gadopentetate dimeglumine could not enable discrimination between normal and atherosclerotic vessel walls (P = .428). PIXE analysis showed higher amounts of gadopentetate dimeglumine than gadofosveset in both atherosclerotic and normal rabbit aortas. Immunohistochemical staining revealed the presence of albumin and increased microvessel density in the vascular walls of atherosclerotic rabbits. CONCLUSION These results suggest that gadofosveset can be used to differentiate between atherosclerotic and normal rabbit vessel walls. SUPPLEMENTAL MATERIAL http://radiology.rsnajnls.org/cgi/content/full/250/3/682/DC1.

Gadofosveset-enhanced magnetic resonance imaging of human carotid atherosclerotic plaques : a proof-of-concept study

Objective:To investigate the potential of gadofosveset-enhanced MR imaging for the characterization of human carotid atherosclerotic plaques. Materials and Methods:Sixteen (9 symptomatic, 7 asymptomatic) patients with 70% to 99% carotid stenosis (according to NASCET criteria) were included (13 men, 3 women, mean age 67.6 years). All patients underwent baseline precontrast MR imaging of the carotid plaque. Immediately after completion of the baseline examination, 0.03 mmol/kg gadofosveset was administered. At 24 hours postinjection, the acquisition was repeated. Twelve patients were scheduled for carotid endarterectomy. Carotid endarterectomy specimens were HE-, CD31-, CD68-, and albumin-stained to correlate signal enhancement with plaque composition, intraplaque microvessel density, and macrophage and albumin content. A random intercept model was used to compare signal enhancement between symptomatic and asymptomatic patients, adjusting for size of various plaque components. This study was approved by the institutional medical ethics committee. All participants gave written informed consent. Results:Signal enhancement (SE) of the plaque was significantly higher in symptomatic patients compared with asymptomatic patients (median log SE 0.182 vs. −0.109, respectively, P < 0.001). A positive association (as expressed by a regression coefficient &bgr; = 0.0035) was found between signal enhancement on the log scale and intraplaque albumin content (P = 0.038). There was no association between signal enhancement and various other plaque components. Conclusion:In this study, the potential of gadofosveset-enhanced human carotid plaque MR imaging for identification of high-risk plaques was demonstrated. Signal enhancement of the plaque after administration of gadofosveset was associated with differences in intraplaque albumin content. Although promising, we emphasize that these results are based on a small patient population. Larger prospective studies are warranted.

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.

Rapid point-of-care breath test for biomarkers of breast cancer and abnormal mammograms.

Background Previous studies have reported volatile organic compounds (VOCs) in breath as biomarkers of breast cancer and abnormal mammograms, apparently resulting from increased oxidative stress and cytochrome p450 induction. We evaluated a six-minute point-of-care breath test for VOC biomarkers in women screened for breast cancer at centers in the USA and the Netherlands. Methods 244 women had a screening mammogram (93/37 normal/abnormal) or a breast biopsy (cancer/no cancer 35/79). A mobile point-of-care system collected and concentrated breath and air VOCs for analysis with gas chromatography and surface acoustic wave detection. Chromatograms were segmented into a time series of alveolar gradients (breath minus room air). Segmental alveolar gradients were ranked as candidate biomarkers by C-statistic value (area under curve [AUC] of receiver operating characteristic [ROC] curve). Multivariate predictive algorithms were constructed employing significant biomarkers identified with multiple Monte Carlo simulations and cross validated with a leave-one-out (LOO) procedure. Results Performance of breath biomarker algorithms was determined in three groups: breast cancer on biopsy versus normal screening mammograms (81.8% sensitivity, 70.0% specificity, accuracy 79% (73% on LOO) [C-statistic value], negative predictive value 99.9%); normal versus abnormal screening mammograms (86.5% sensitivity, 66.7% specificity, accuracy 83%, 62% on LOO); and cancer versus no cancer on breast biopsy (75.8% sensitivity, 74.0% specificity, accuracy 78%, 67% on LOO). Conclusions A pilot study of a six-minute point-of-care breath test for volatile biomarkers accurately identified women with breast cancer and with abnormal mammograms. Breath testing could potentially reduce the number of needless mammograms without loss of diagnostic sensitivity.

Radiation Exposure of Contrast-Enhanced Spectral Mammography Compared With Full-Field Digital Mammography

ObjectivesContrast-enhanced spectral mammography (CESM) shows promising initial results but comes at the cost of increased dose as compared with full-field digital mammography (FFDM). We aimed to quantitatively assess the dose increase of CESM in comparison with FFDM. Materials and MethodsRadiation exposure–related data (such as kilovoltage, compressed breast thickness, glandularity, entrance skin air kerma (ESAK), and average glandular dose (AGD) were retrieved for 47 CESM and 715 FFDM patients. All examinations were performed on 1 mammography unit. Radiation dose values reported by the unit were validated by phantom measurements. Descriptive statistics of the patient data were generated using a statistical software package. ResultsDose values reported by the mammography unit were in good qualitative agreement with those of phantom measurements. Mean ESAK was 10.5 mGy for a CESM exposure and 7.46 mGy for an FFDM exposure. Mean AGD for a CESM exposure was 2.80 mGy and 1.55 mGy for an FFDM exposure. ConclusionsCompared with our institutional FFDM, the AGD of a single CESM exposure is increased by 1.25 mGy (+81%), whereas ESAK is increased by 3.07 mGy (+41%). Dose values of both techniques meet the recommendations for maximum dose in mammography.

The diagnostic performance of sentinel lymph node biopsy in pathologically confirmed node positive breast cancer patients after neoadjuvant systemic therapy: A systematic review and meta-analysis

PURPOSE To provide a systematic review and meta-analysis of studies investigating sentinel lymph node biopsy after neoadjuvant systemic therapy in pathologically confirmed node positive breast cancer patients. METHODS Pubmed and Embase databases were searched until June 19th, 2015. All abstracts were read and data extraction was performed by two independent readers. A random-effects model was used to pool the proportion for identification rate, false-negative rate (FNR) and axillary pCR with 95% confidence intervals. Subgroup analyses affirmed potential confounders for identification rate and FNR. RESULTS A total of 997 abstracts were identified and eventually eight studies were included. Pooled estimates were 92.3% (90.8-93.7%) for identification rate, 15.1% (12.7-17.6%) for FNR and 36.8% (34.2-39.5%) for axillary pCR. After subgroup analysis, FNR is significantly worse if one sentinel node was removed compared to two or more sentinel nodes (23.9% versus 10.4%, p = 0.026) and if studies contained clinically nodal stage 1-3, compared to studies with clinically nodal stage 1-2 patients (21.4 versus 13.1%, p = 0.049). Other factors, including single tracer mapping and the definition of axillary pCR, were not significantly different. CONCLUSION Based on current evidence it seems not justified to omit further axillary treatment in every clinically node positive breast cancer patients with a negative sentinel lymph node biopsy after neoadjuvant systemic therapy.

Computer-aided Detection of Masses at Mammography: Interactive Decision Support versus Prompts

PURPOSE To compare effectiveness of an interactive computer-aided detection (CAD) system, in which CAD marks and their associated suspiciousness scores remain hidden unless their location is queried by the reader, with the effect of traditional CAD prompts used in current clinical practice for the detection of malignant masses on full-field digital mammograms. MATERIALS AND METHODS The requirement for institutional review board approval was waived for this retrospective observer study. Nine certified screening radiologists and three residents who were trained in breast imaging read 200 studies (63 studies containing at least one screen-detected mass, 17 false-negative studies, 20 false-positive studies, and 100 normal studies) twice, once with CAD prompts and once with interactive CAD. Localized findings were reported and scored by the readers. In the prompted mode, findings were recorded before and after activation of CAD. The partial area under the location receiver operating characteristic (ROC) curve for an interval of low false-positive fractions typical for screening, from 0 to 0.2, was computed for each reader and each mode. Differences in reader performance were analyzed by using software. RESULTS The average partial area under the location ROC curve with unaided reading was 0.57, and it increased to 0.62 with interactive CAD, while it remained unaffected by prompts. The difference in reader performance for unaided reading versus interactive CAD was statistically significant (P = .009). CONCLUSION When used as decision support, interactive use of CAD for malignant masses on mammograms may be more effective than the current use of CAD, which is aimed at the prevention of perceptual oversights.