Surveillance of Women with the BRCA1 or BRCA2 Mutation by Using Biannual Automated Breast US, MR Imaging, and Mammography.

Purpose To evaluate a multimodal surveillance regimen including yearly full-field digital (FFD) mammography, dynamic contrast agent-enhanced (DCE) magnetic resonance (MR) imaging, and biannual automated breast (AB) ultrasonography (US) in women with BRCA1 and BRCA2 mutations. Materials and Methods This prospective multicenter trial enrolled 296 carriers of the BRCA mutation (153 BRCA1 and 128 BRCA2 carriers, and 15 women with first-degree untested relatives) between September 2010 and November 2012, with follow-up until November 2015. Participants underwent 2 years of intensified surveillance including biannual AB US, and routine yearly DCE MR imaging and FFD mammography. The surveillance performance for each modality and possible combinations were determined. Results Breast cancer was screening-detected in 16 women (age range, 33-58 years). Three interval cancers were detected by self-examination, all in carriers of the BRCA1 mutation under age 43 years. One cancer was detected in a carrier of the BRCA1 mutation with a palpable abnormality in the contralateral breast. One incidental breast cancer was detected in a prophylactic mastectomy specimen. Respectively, sensitivity of DCE MR imaging, FFD mammography, and AB US was 68.1% (14 of 21; 95% confidence interval [CI]: 42.9%, 85.8%), 37.2% (eight of 21; 95% CI: 19.8%, 58.7%), and 32.1% (seven of 21; 95% CI: 16.1%, 53.8%); specificity was 95.0% (643 of 682; 95% CI: 92.7%, 96.5%), 98.1% (638 of 652; 95% CI: 96.7%, 98.9%), and 95.1% (1030 of 1088; 95% CI: 93.5%, 96.3%); cancer detection rate was 2.0% (14 of 702), 1.2% (eight of 671), and 1.0% (seven of 711) per 100 women-years; and positive predictive value was 25.2% (14 of 54), 33.7% (nine of 23), and 9.5% (seven of 68). DCE MR imaging and FFD mammography combined yielded the highest sensitivity of 76.3% (16 of 21; 95% CI: 53.8%, 89.9%) and specificity of 93.6% (643 of 691; 95% CI: 91.3%, 95.3%). AB US did not depict additional cancers. FFD mammography yielded no additional cancers in women younger than 43 years, the mean age at diagnosis. In carriers of the BRCA2 mutation, sensitivity of FFD mammography with DCE MR imaging surveillance was 90.9% (10 of 11; 95% CI: 72.7%, 100%) and 60.0% (six of 10; 95% CI: 30.0%, 90.0%) in carriers of the BRCA1 mutation because of the high interval cancer rate in carriers of the BRCA1 mutation. Conclusion AB US may not be of added value to yearly FFD mammography and DCE MR imaging surveillance of carriers of the BRCA mutation. Study results suggest that carriers of the BRCA mutation younger than 40 years may not benefit from FFD mammography surveillance in addition to DCE MR imaging. © RSNA, 2017 Online supplemental material is available for this article.

Prophylactic vaccines are potent activators of monocyte-derived dendritic cells and drive effective anti-tumor responses in melanoma patients at the cost of toxicity.

Dendritic cell (DC)-based immunotherapy is explored worldwide in cancer patients, predominantly with DC matured with pro-inflammatory cytokines and prostaglandin E2. We studied the safety and efficacy of vaccination with monocyte-derived DC matured with a cocktail of prophylactic vaccines that contain clinical-grade Toll-like receptor ligands (BCG, Typhim, Act-HIB) and prostaglandin E2 (VAC-DC). Stage III and IV melanoma patients were vaccinated via intranodal injection (12 patients) or combined intradermal/intravenous injection (16 patients) with VAC-DC loaded with keyhole limpet hemocyanin (KLH) and mRNA encoding tumor antigens gp100 and tyrosinase. Tumor antigen-specific T cell responses were monitored in blood and skin-test infiltrating-lymphocyte cultures. Almost all patients mounted prophylactic vaccine- or KLH-specific immune responses. Both after intranodal injection and after intradermal/intravenous injection, tumor antigen-specific immune responses were detected, which coincide with longer overall survival in stage IV melanoma patients. VAC-DC induce local and systemic CTC grade 2 and 3 toxicity, which is most likely caused by BCG in the maturation cocktail. The side effects were self-limiting or resolved upon a short period of systemic steroid therapy. We conclude that VAC-DC can induce functional tumor-specific responses. Unfortunately, toxicity observed after vaccination precludes the general application of VAC-DC, since in DC maturated with prophylactic vaccines BCG appears to be essential in the maturation cocktail.

Early identification of antigen-specific immune responses in vivo by [18F]-labeled 3'-fluoro-3'-deoxy-thymidine ([18F]FLT) PET imaging.

Current biomarkers are unable to adequately predict vaccine-induced immune protection in humans with infectious disease or cancer. However, timely and adequate assessment of antigen-specific immune responses is critical for successful vaccine development. Therefore, we have developed a method for the direct assessment of immune responses in vivo in a clinical setting. Melanoma patients with lymph node (LN) metastases received dendritic cell (DC) vaccine therapy, injected intranodally, followed by [(18)F]-labeled 3'-fluoro-3'-deoxy-thymidine ([(18)F]FLT) PET at varying time points after vaccination. Control LNs received saline or DCs without antigen. De novo immune responses were readily visualized in treated LNs early after the prime vaccination, and these signals persisted for up to 3 wk. This selective [(18)F]FLT uptake was markedly absent in control LNs, although tracer uptake in treated LNs increased profoundly with as little as 4.5 × 10(5) DCs. Immunohistochemical staining confirmed injected DC dispersion to T-cell areas and resultant activation of CD4(+) and CD8(+) T cells. The level of LN tracer uptake significantly correlates to the level of circulating antigen-specific IgG antibodies and antigen-specific proliferation of T cells in peripheral blood. Furthermore, this correlation was not observed with [(18)F]-labeled fluoro-2-deoxy-2-D-glucose. Therefore, [(18)F]FLT PET offers a sensitive tool to study the kinetics, localization, and involvement of lymphocyte subsets in response to vaccination. This technique allows for early discrimination of responding from nonresponding patients in anti-cancer vaccination and aid physicians in individualized decisionmaking.

18F-2-deoxy-2-fluoro-D-glucose positron emission tomography, computed tomography, and magnetic resonance imaging for the detection of experimental colorectal liver metastases.

During the treatment of colorectal liver metastases, evaluation of treatment efficacy is of the utmost importance for decision making. The aim of the present study was to explore the ability of preclinical imaging modalities to detect experimental liver metastases. Nine male Wag/Rij rats underwent a laparotomy with intraportal injection of CC531 tumor cells. On days 7, 10, and 14 after tumor induction, sequential positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging (MRI) scans were acquired of each rat. At each time point, three rats were euthanized and the metastases in the liver were documented histologically. Topographically, the liver was divided into eight segments and the image findings were compared on a segment-by-segment basis with the histopathologic findings. Sixty-four liver segments were analyzed, 20 of which contained tumor deposits. The overall sensitivity of PET, CT, and MRI was 30%, 25%, and 20%, respectively. For the detection of tumors with a histologic diameter exceeding 1 mm (n  =  8), the sensitivity of PET, CT, and MRI was 63%, 38%, and 38%, respectively. The overall specificity of PET, CT, and MRI was 98%, 100%, and 93%, respectively. This study showed encouraging detectability and sensitivity for preclinical imaging of small liver tumors and provides valuable information on the imaging techniques for designing future protocols.

MR-guided breast biopsy at 3T: diagnostic yield of large core needle biopsy compared with vacuum-assisted biopsy.

OBJECTIVE: The purpose of this study was to evaluate two MR-guided biopsy techniques at 3 T, large core needle breast biopsy (LCNB) and vacuum-assisted breast biopsy (VAB) and to compare the diagnostic yield and rate of complications to determine the optimal biopsy technique at 3 T. METHODS: 55 LCNB and 64 VAB were consecutively performed. Benign biopsy results were verified by retrospective correlation of histology, with pre-interventional, post-interventional MRI studies and follow-up and were classified as representative or non-representative. Time to follow-up was up to 2 years for the considered non-representative benign lesions. Statistical analysis was performed using the Chi-squared test. RESULTS: LCNB was technically successful in 100% of patients (55/55) and VAB in 98% of patients (63/64). Histopathological analysis resulted in 45 (82%) benign, 3 (5%) high-risk and 7 (13%) malignant lesions for LCNB and 43 (67%) benign, 3 (5%) high-risk and 18 (28%) malignant lesions. Distribution was significantly different (p < 0.001), favouring VAB over LCNB. CONCLUSION: Because of the substantially higher diagnostic yield and certainty of a benign diagnosis, VAB is the optimal biopsy technique at 3 T. LCNB should be considered when VAB is not feasible.

Using computer-aided detection in mammography as a decision support.

OBJECTIVE: To evaluate an interactive computer-aided detection (CAD) system for reading mammograms to improve decision making. METHODS: A dedicated mammographic workstation has been developed in which readers can probe image locations for the presence of CAD information. If present, CAD findings are displayed with the computed malignancy rating. A reader study was conducted in which four screening radiologists and five non-radiologists participated to study the effect of this system on detection performance. The participants read 120 cases of which 40 cases had a malignant mass that was missed at the original screening. The readers read each mammogram both with and without CAD in separate sessions. Each reader reported localized findings and assigned a malignancy score per finding. Mean sensitivity was computed in an interval of false-positive fractions less than 10%. RESULTS: Mean sensitivity was 25.1% in the sessions without CAD and 34.8% in the CAD-assisted sessions. The increase in detection performance was significant (p = 0.012). Average reading time was 84.7 ± 61.5 s/case in the unaided sessions and was not significantly higher when interactive CAD was used (85.9 ± 57.8 s/case). CONCLUSION: Interactive use of CAD in mammography may be more effective than traditional CAD for improving mass detection without affecting reading time.

Blood-derived dendritic cell vaccinations induce immune responses that correlate with clinical outcome in patients with chemo-naive castration-resistant prostate cancer.

BACKGROUND: Clinical benefit of cellular immunotherapy has been shown in patients with castration-resistant prostate cancer (CRPC). We investigated the immunological response and clinical outcome of vaccination with blood-derived CD1c+ myeloid dendritic cells (mDCs; cDC2) and plasmacytoid DCs (pDCs). METHODS: In this randomized phase IIa trial, 21 chemo-naive CRPC patients received maximally 9 vaccinations with mature mDCs, pDCs or a combination of mDCs plus pDCs. DCs were stimulated with protamine/mRNA and loaded with tumor-associated antigens NY-ESO-1, MAGE-C2 and MUC1. Primary endpoint was the immunological response after DC vaccination, which was monitored in peripheral blood and in T cell cultures of biopsies of post-treatment delayed-type hypersensitivity-skin tests. Main secondary endpoints were safety, feasibility, radiological PFS (rPFS) and overall survival. Radiological responses were assessed by MRIs and contrast-enhanced 68Ga-prostate-specific membrane antigen PET/CT, according to RECIST 1.1, PCWG2 criteria and immune-related response criteria. RESULTS: Both tetramer/dextramer-positive (dm+) and IFN-γ-producing (IFN-γ+) antigen specific T cells were detected more frequently in skin biopsies of patients with radiological non-progressive disease (5/13 patients; 38%) compared to patients with progressive disease (0/8 patients; 0%). In these patients with vaccination enhanced dm+ and IFN-γ+ antigen-specific T cells median rPFS was 18.8 months (n = 5) vs. 5.1 months (n = 16) in patients without IFN-γ-producing antigen-specific T cells (p = 0.02). The overall median rPFS was 9.5 months. All DC vaccines were well tolerated with grade 1-2 toxicity. CONCLUSIONS: Immunotherapy with blood-derived DC subsets was feasible and safe and induced functional antigen-specific T cells. The presence of functional antigen-specific T cells correlated with an improved clinical outcome. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02692976, registered 26 February 2016, retrospectively registered.

Time to enhancement derived from ultrafast breast MRI as a novel parameter to discriminate benign from malignant breast lesions.

OBJECTIVES: To investigate time to enhancement (TTE) as novel dynamic parameter for lesion classification in breast magnetic resonance imaging (MRI). METHODS: In this retrospective study, 157 women with 195 enhancing abnormalities (99 malignant and 96 benign) were included. All patients underwent a bi-temporal MRI protocol that included ultrafast time-resolved angiography with stochastic trajectory (TWIST) acquisitions (1.0×0.9×2.5mm, temporal resolution 4.32s), during the inflow of contrast agent. TTE derived from TWIST series and relative enhancement versus time curve type derived from volumetric interpolated breath-hold examination (VIBE) series were assessed and combined with basic morphological information to differentiate benign from malignant lesions. Receiver operating characteristic analysis and kappa statistics were applied. RESULTS: TTE had a significantly better discriminative ability than curve type (p<0.001 and p=0.026 for reader 1 and 2, respectively). Including morphology, sensitivity of TWIST and VIBE assessment was equivalent (p=0.549 and p=0.344, respectively). Specificity and diagnostic accuracy were significantly higher for TWIST than for VIBE assessment (p<0.001). Inter-reader agreement in differentiating malignant from benign lesions was almost perfect for TWIST evaluation (κ=0.86) and substantial for conventional assessment (κ=0.75). CONCLUSIONS: TTE derived from ultrafast TWIST acquisitions is a valuable parameter that allows robust differentiation between malignant and benign breast lesions with high accuracy.

Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells.

PURPOSE: Thus far, dendritic cell (DC)-based immunotherapy of cancer was primarily based on in vitro-generated monocyte-derived DCs, which require extensive in vitro manipulation. Here, we report on a clinical study exploiting primary CD1c(+) myeloid DCs, naturally circulating in the blood. EXPERIMENTAL DESIGN: Fourteen stage IV melanoma patients, without previous systemic treatment for metastatic disease, received autologous CD1c(+) myeloid DCs, activated by only brief (16 hours) ex vivo culture and loaded with tumor-associated antigens of tyrosinase and gp100. RESULTS: Our results show that therapeutic vaccination against melanoma with small amounts (3-10 × 10(6)) of myeloid DCs is feasible and without substantial toxicity. Four of 14 patients showed long-term progression-free survival (12-35 months), which directly correlated with the development of multifunctional CD8(+) T-cell responses in three of these patients. In particular, high CD107a expression, indicative for cytolytic activity, and IFNγ as well as TNFα and CCL4 production was observed. Apparently, these T-cell responses are essential to induce tumor regression and promote long-term survival by stalling tumor growth. CONCLUSIONS: We show that vaccination of metastatic melanoma patients with primary myeloid DCs is feasible and safe and results in induction of effective antitumor immune responses that coincide with improved progression-free survival. Clin Cancer Res; 22(9); 2155-66. ©2015 AACR.

A novel approach to contrast-enhanced breast magnetic resonance imaging for screening: high-resolution ultrafast dynamic imaging.

OBJECTIVES: The use of breast magnetic resonance imaging (MRI) as screening tool has been stalled by high examination costs. Scan protocols have lengthened to optimize specificity. Modern view-sharing sequences now enable ultrafast dynamic whole-breast MRI, allowing much shorter and more cost-effective procedures. This study evaluates whether dynamic information from ultrafast breast MRI can be used to replace standard dynamic information to preserve accuracy. MATERIALS AND METHODS: We interleaved 20 ultrafast time-resolved angiography with stochastic trajectory (TWIST) acquisitions (0.9 × 1 × 2.5 mm, temporal resolution, 4.3 seconds) during contrast inflow in a regular high-resolution dynamic MRI protocol. A total of 160 consecutive patients with 199 enhancing abnormalities (95 benign and 104 malignant) were included. The maximum slope of the relative enhancement versus time curve (MS) obtained from the TWIST and curve type obtained from the regular dynamic sequence as defined in the breast imaging reporting and data system (BIRADS) lexicon were recorded. Diagnostic performance was compared using receiver operating characteristic analysis. RESULTS: All lesions were visible on both the TWIST and standard series. Maximum slope allows discrimination between benign and malignant disease with high accuracy (area under the curve, 0.829). Types of MS were defined in analogy to BIRADS curve types: MS type 3 implies a high risk of malignancy (MS >13.3%/s; specificity, 85%), MS type 2 yields intermediate risk (MS <13.3%/s and >6.4%/s), and MS type 1 implies a low risk (MS <6.4%/s; sensitivity, 90%). This simplification provides a much higher accuracy than the much lengthier BIRADS curve type analysis does (area under the curve, 0.812 vs 0.692; P = 0.0061). CONCLUSIONS: Ultrafast dynamic breast MRI allows detection of breast lesions and classification with high accuracy using MS. This allows substantial shortening of scan protocols and hence reduces imaging costs, which is beneficial especially for screening.

MRI-guided breast biopsy at 3T using a dedicated large core biopsy set: feasibility and initial results.

OBJECTIVE: The increasing importance of breast MRI in the diagnostic processes concerning breast cancer yield often lesions that are visible on MRI only. To assess the nature of these lesions, pathologic analysis is necessary. Therefore, MR-guided biopsy should be available. Breast MRI at 3T has shown advantage over 1.5T. Unfortunately, current equipment for MR-guided biopsy is better suited for intervention at 1.5T due to the danger of heating titanium co-axial sleeves and large susceptibility artifacts. We evaluated a dedicated 3T breast biopsy set that uses plastic coaxial needles to overcome these problems. MATERIALS AND METHODS: We performed MRI-guided breast biopsy in 23 women with 24 MRI-only visible breast lesions at 3T. Biopsy procedures were performed with plastic coaxial needles in a closed bore 3T clinical MR system on a dedicated phased array breast coil with a commercially available add-on stereotactic biopsy device. RESULTS: Width of the needle artifact was 2mm in all 24 cases. Biopsy procedure was completed between 35 and 67 min. The procedure was judged moderately easy in 12 and normal in 10 cases. One procedure was judged difficult and there was one technical failure. CONCLUSION: MRI-guided breast biopsy at 3T is a fast and accurate procedure. The plastic coaxial needles reduce the susceptibility artifact largely and do not increase the difficulty of the procedure. The diagnostic yield is at least equal to the diagnostic yield of the same procedure at 1.5T. Therefore, this technique can be safely used for lesions only visible at 3T MRI.

[3-D ultrasound of the breast: less dependent on the investigator]. / 3D-echografie van de mamma: minder afhankelijk van onderzoeker.

Three-dimensional (3-D) ultrasound is a technique, in which almost the entire breast is automatically scanned. Data sets can be stored and reviewed at a later date. This almost completely eliminates the subjective character of conventional ultrasound, enabling a more reliable review and follow-up. 3-D ultrasound can be implemented in daily radiological practice and could possibly be used in population screening programmes for breast cancer.