Silicone implant and fibrous capsule assessment based on water-fat-silicone chemical shift encoding-based species separation in breast MRI.

BACKGROUND: With rising breast augmentations worldwide, there is an increasing clinical need for an early and accurate detection of implant complications. PURPOSE: To compare the quality of chemical shift encoding-based (CSE) water-fat-silicone separation compared to double inversion recovery (DIR) silicone-only imaging in breast magnetic resonance imaging (MRI). MATERIAL AND METHODS: This retrospective, single-center study included women with silicone implants subjected to 3-T MRI between January 2021 and March 2022. MRI included (i) two-dimensional silicone-only T2-weighted turbo spin echo DIR acquisition and (ii) three-dimensional CSE imaging based on multi-echo gradient-echo sequence enabling water-, fat-, and silicone-image separation. Images were evaluated and compared by three independent radiologists using a clinically established rating including differentiability of the silicone implant, visibility and contouring of the adjacent fibrous capsule, and accuracy of intralesional folds in a ranking of 1-5. The apparent contrast-to-noise (aCNR) was calculated. RESULTS: In 71 women, the average quality of water-fat-silicone images from CSE imaging was assessed as "good" (assessment 4 ± 0.9). In 68 (96%) patients, CSE imaging achieved a concise delineation of the silicone implant and precise visualization of the fibrous capsule that was not distinguishable in DIR imaging. Implant ruptures were more easily detected in CSE imaging. The aCNR was higher in CSE compared to DIR imaging (18.43 ± 9.8 vs. 14.73 ± 2.5; P = 0.002). CONCLUSION: Intrinsically co-registered water-fat-silicone-separated CSE-based images enable a reliable assessment of silicone implants. The simultaneously improved differentiability of the implant and fibrous capsule may provide clinicians with a valuable tool for an accurate evaluation of implant integrity and early detection of potential complications.

X-ray imageable, drug-loaded hydrogel that forms at body temperature for image-guided, needle-based locoregional drug delivery.

Liver cancer ranks as the fifth leading cause of cancer-related death globally. Direct intratumoral injections of anti-cancer therapeutics may improve therapeutic efficacy and mitigate adverse effects compared to intravenous injections. Some challenges of intratumoral injections are that the liquid drug formulation may not remain localized and have unpredictable volumetric distribution. Thus, drug delivery varies widely, highly-dependent upon technique. An X-ray imageable poloxamer 407 (POL)-based drug delivery gel was developed and characterized, enabling real-time feedback. Utilizing three needle devices, POL or a control iodinated contrast solution were injected into an ex vivo bovine liver. The 3D distribution was assessed with cone beam computed tomography (CBCT). The 3D distribution of POL gels demonstrated localized spherical morphologies regardless of the injection rate. In addition, the gel 3D conformal distribution could be intentionally altered, depending on the injection technique. When doxorubicin (DOX) was loaded into the POL and injected, DOX distribution on optical imaging matched iodine distribution on CBCT suggesting spatial alignment of DOX and iodine localization in tissue. The controllability and localized deposition of this formulation may ultimately reduce the dependence on operator technique, reduce systemic side effects, and facilitate reproducibility across treatments, through more predictable standardized delivery.

Smart goggles augmented reality CT-US fusion compared to conventional fusion navigation for percutaneous needle insertion.

PURPOSE: Targeting accuracy determines outcomes for percutaneous needle interventions. Augmented reality (AR) in IR may improve procedural guidance and facilitate access to complex locations. This study aimed to evaluate percutaneous needle placement accuracy using a goggle-based AR system compared to an ultrasound (US)-based fusion navigation system. METHODS: Six interventional radiologists performed 24 independent needle placements in an anthropomorphic phantom (CIRS 057A) in four needle guidance cohorts (n = 6 each): (1) US-based fusion, (2) goggle-based AR with stereoscopically projected anatomy (AR-overlay), (3) goggle AR without the projection (AR-plain), and (4) CT-guided freehand. US-based fusion included US/CT registration with electromagnetic (EM) needle, transducer, and patient tracking. For AR-overlay, US, EM-tracked needle, stereoscopic anatomical structures and targets were superimposed over the phantom. Needle placement accuracy (distance from needle tip to target center), placement time (from skin puncture to final position), and procedure time (time to completion) were measured. RESULTS: Mean needle placement accuracy using US-based fusion, AR-overlay, AR-plain, and freehand was 4.5 ± 1.7 mm, 7.0 ± 4.7 mm, 4.7 ± 1.7 mm, and 9.2 ± 5.8 mm, respectively. AR-plain demonstrated comparable accuracy to US-based fusion (p = 0.7) and AR-overlay (p = 0.06). Excluding two outliers, AR-overlay accuracy became 5.9 ± 2.6 mm. US-based fusion had the highest mean placement time (44.3 ± 27.7 s) compared to all navigation cohorts (p < 0.001). Longest procedure times were recorded with AR-overlay (34 ± 10.2 min) compared to AR-plain (22.7 ± 8.6 min, p = 0.09), US-based fusion (19.5 ± 5.6 min, p = 0.02), and freehand (14.8 ± 1.6 min, p = 0.002). CONCLUSION: Goggle-based AR showed no difference in needle placement accuracy compared to the commercially available US-based fusion navigation platform. Differences in accuracy and procedure times were apparent with different display modes (with/without stereoscopic projections). The AR-based projection of the US and needle trajectory over the body may be a helpful tool to enhance visuospatial orientation. Thus, this study refines the potential role of AR for needle placements, which may serve as a catalyst for informed implementation of AR techniques in IR.

X-ray imageable, drug-loaded hydrogel that forms at body temperature for image-guided, needle- based locoregional drug delivery.

Liver cancer ranks as the fifth leading cause of cancer-related death globally. Direct intratumoral injections of anti-cancer therapeutics may improve therapeutic efficacy and mitigate adverse effects compared to intravenous injections. Some challenges of intratumoral injections are that the liquid drug formulation may not remain localized and have unpredictable volumetric distribution. Thus, drug delivery varies widely, highly-dependent upon technique. An x-ray imageable poloxamer 407 (POL)-based drug delivery gel was developed and characterized, enabling real-time feedback. Utilizing three needle devices, POL or a control iodinated contrast solution were injected into an ex vivo bovine liver. The 3D distribution was assessed with cone beam computed tomography (CBCT). The 3D distribution of POL gels demonstrated localized spherical morphologies regardless of the injection rate. In addition, the gel 3D conformal distribution could be intentionally altered, depending on the injection technique. When doxorubicin (DOX) was loaded into the POL and injected, DOX distribution on optical imaging matched iodine distribution on CBCT suggesting spatial alignment of DOX and iodine localization in tissue. The controllability and localized deposition of this formulation may ultimately reduce the dependence on operator technique, reduce systemic side effects, and facilitate reproducibility across treatments, through more predictable standardized delivery.

Robust breast quantitative susceptibility mapping in the presence of silicone.

PURPOSE: To (a) develop a preconditioned water-fat-silicone total field inversion (wfsTFI) algorithm that directly estimates the susceptibility map from complex multi-echo data in the breast in the presence of silicone and to (b) evaluate the performance of wfsTFI for breast quantitative susceptibility mapping (QSM) in silico and in vivo in comparison with formerly proposed methods. METHODS: Numerical simulations and in vivo multi-echo gradient echo breast measurements were performed to compare wfsTFI to a previously proposed field map-based linear total field inversion algorithm (lTFI) with and without the consideration of the chemical shift of silicone in the field map estimation step. Specifically, a simulation based on an in vivo scan and data from five patients were included in the analysis. RESULTS: In the simulation, wfsTFI is able to significantly decrease the normalized root mean square error from lTFI without (4.46) and with (1.77) the consideration of the chemical shift of silicone to 0.68. Both the in silico and in vivo wfsTFI susceptibility maps show reduced shadowing artifacts in local tissue adjacent to silicone, reduced streaking artifacts and no erroneous single voxels of diamagnetic susceptibility in proximity to silicone. CONCLUSION: The proposed wfsTFI method can automatically distinguish between subjects with and without silicone. Furthermore wfsTFI accounts for the presence of silicone in the QSM dipole inversion and allows for the robust estimation of susceptibility in proximity to silicone breast implants and hence allows the visualization of structures that would otherwise be dominated by artifacts on susceptibility maps.

Assessing breast density using the chemical-shift encoding-based proton density fat fraction in 3-T MRI.

OBJECTIVES: There is a clinical need for a non-ionizing, quantitative assessment of breast density, as one of the strongest independent risk factors for breast cancer. This study aims to establish proton density fat fraction (PDFF) as a quantitative biomarker for fat tissue concentration in breast MRI and correlate mean breast PDFF to mammography. METHODS: In this retrospective study, 193 women were routinely subjected to 3-T MRI using a six-echo chemical shift encoding-based water-fat sequence. Water-fat separation was based on a signal model accounting for a single T2* decay and a pre-calibrated 7-peak fat spectrum resulting in volumetric fat-only, water-only images, PDFF- and T2*-values. After semi-automated breast segmentation, PDFF and T2* values were determined for the entire breast and fibroglandular tissue. The mammographic and MRI-based breast density was classified by visual estimation using the American College of Radiology Breast Imaging Reporting and Data System categories (ACR A-D). RESULTS: The PDFF negatively correlated with mammographic and MRI breast density measurements (Spearman rho: -0.74, p < .001) and revealed a significant distinction between all four ACR categories. Mean T2* of the fibroglandular tissue correlated with increasing ACR categories (Spearman rho: 0.34, p < .001). The PDFF of the fibroglandular tissue showed a correlation with age (Pearson rho: 0.56, p = .03). CONCLUSION: The proposed breast PDFF as an automated tissue fat concentration measurement is comparable with mammographic breast density estimations. Therefore, it is a promising approach to an accurate, user-independent, and non-ionizing breast density assessment that could be easily incorporated into clinical routine breast MRI exams. KEY POINTS: • The proposed PDFF strongly negatively correlates with visually determined mammographic and MRI-based breast density estimations and therefore allows for an accurate, non-ionizing, and user-independent breast density measurement. • In combination with T2*, the PDFF can be used to track structural alterations in the composition of breast tissue for an individualized risk assessment for breast cancer.

Hierarchical Multi-Resolution Graph-Cuts for Water-Fat-Silicone Separation in Breast MRI.

Water-fat separation is a non-linear non-convex parameter estimation problem in magnetic resonance imaging typically solved using spatial constraints. However, there is still limited knowledge on how to separate in vivo three chemical species in the presence of magnetic field inhomogeneities. The proposed method uses multiple graph-cuts in a hierarchical multi-resolution framework to perform robust chemical species separation in the breast for subjects with and without silicone implants. Experimental results show that the proposed method can decrease the computational time for water-fat separation and perform accurate water-fat-silicone separation with only a limited number of acquired echo images at 3 T. The silicone-separated images have an improved spatial resolution and image contrast compared to conventional scans used for regular monitoring of the silicone implant's integrity.

Optimization of the BCLC Staging System for Locoregional Therapy for Hepatocellular Carcinoma by Using Quantitative Tumor Burden Imaging Biomarkers at MRI.

Background Patients with intermediate- and advanced-stage hepatocellular carcinoma (HCC) represent a highly heterogeneous patient collective with substantial differences in overall survival. Purpose To evaluate enhancing tumor volume (ETV) and enhancing tumor burden (ETB) as new criteria within the Barcelona Clinic Liver Cancer (BCLC) staging system for optimized allocation of patients with intermediate- and advanced-stage HCC to undergo transarterial chemoembolization (TACE). Materials and Methods In this retrospective study, 682 patients with HCC who underwent conventional TACE or TACE with drug-eluting beads from January 2000 to December 2014 were evaluated. Quantitative three-dimensional analysis of contrast-enhanced MRI was performed to determine thresholds of ETV and ETB (ratio of ETV to normal liver volume). Patients with ETV below 65 cm3 or ETB below 4% were reassigned to BCLC Bn, whereas patients with ETV or ETB above the determined cutoffs were restratified or remained in BCLC Cn by means of stepwise verification of the median overall survival (mOS). Results This study included 494 patients (median age, 62 years [IQR, 56-71 years]; 401 men). Originally, 123 patients were classified as BCLC B with mOS of 24.3 months (95% CI: 21.4, 32.9) and 371 patients as BCLC C with mOS of 11.9 months (95% CI: 10.5, 14.8). The mOS of all included patients (including the BCLC B and C groups) was 15 months (95% CI: 12.3, 17.2). A total of 152 patients with BCLC C tumors were restratified into a new BCLC Bn class, in which the mOS was then 25.1 months (95% CI: 21.8, 29.7; P < .001). The mOS of the remaining patients (ie, BCLC Cn group) (n = 222; ETV ≥65 cm3 or ETB ≥4%) was 8.4 months (95% CI: 6.1, 11.2). Conclusion Substratification of patients with intermediate- and advanced-stage hepatocellular carcinoma according to three-dimensional quantitative tumor burden identified patients with a survival benefit from transarterial chemoembolization before therapy. © RSNA, 2022 Online supplemental material is available for this article.

Impact of Chemoembolic Regimen on Immune Cell Recruitment and Immune Checkpoint Marker Expression following Transcatheter Arterial Chemoembolization in a VX2 Rabbit Liver Tumor Model.

PURPOSE: To characterize the effects of commonly used transcatheter arterial chemoembolization (TACE) regimens on the immune response and immune checkpoint marker expression using a VX2 rabbit liver tumor model. MATERIALS AND METHODS: Twenty-four VX2 liver tumor-bearing New Zealand white rabbits were assigned to 7 groups (n = 3 per group) undergoing locoregional therapy as follows: (a) bicarbonate infusion without embolization, (b) conventional TACE (cTACE) using a water-in-oil emulsion containing doxorubicin mixed 1:2 with Lipiodol, drug-eluting embolic-TACE with either (c) idarubicin-eluting Oncozene microspheres (40 µm) or (d) doxorubicin-eluting Lumi beads (40-90 µm). For each therapy arm (b-d), a tandem set of 3 animals with additional bicarbonate infusion before TACE was added, to evaluate the effect of pH modification on the immune response. Three untreated rabbits served as controls. Tissue was harvested 24 hours after treatment, followed by digital immunohistochemistry quantification (counts/µm2 ± SEM) of tumor-infiltrating cluster of differentiation 3+ T-lymphocytes, human leukocyte antigen DR type antigen-presenting cells (APCs), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), and programmed cell death protein-1 (PD-1)/PD-1 ligand (PD-L1) pathway axis expression. RESULTS: Lumi-bead TACE induced significantly more intratumoral T-cell and APC infiltration than cTACE and Oncozene-microsphere TACE. Additionally, tumors treated with Lumi-bead TACE expressed significantly higher intratumoral immune checkpoint markers compared with cTACE and Oncozene-microsphere TACE. Neoadjuvant bicarbonate demonstrated the most pronounced effect on cTACE and resulted in a significant increase in intratumoral cluster of differentiation 3+ T-cell infiltration compared with cTACE alone. CONCLUSIONS: This preclinical study revealed significant differences in evoked tumor immunogenicity depending on the choice of chemoembolic regimen for TACE.

Comparison of metabolic and immunologic responses to transarterial chemoembolization with different chemoembolic regimens in a rabbit VX2 liver tumor model.

OBJECTIVES: The goal of this study was to investigate the effects of TACE using Lipiodol, Oncozene™ drug-eluting embolics (DEEs), or LUMI™-DEEs alone, or combined with bicarbonate on the metabolic and immunological tumor microenvironment in a rabbit VX2 tumor model. METHODS: VX2 liver tumor-bearing rabbits were assigned to five groups. MRI and extracellular pH (pHe) mapping using Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) were performed before and after intra-arterial therapy with conventional TACE (cTACE), DEE-TACE with Idarubicin-eluting Oncozene™-DEEs, or Doxorubicin-eluting LUMI™-DEEs, each with or without prior bicarbonate infusion, and in untreated rabbits or treated with intra-arterial bicarbonate only. Imaging results were validated with immunohistochemistry (IHC) staining of cell viability (PCNA, TUNEL) and immune response (HLA-DR, CD3). Statistical analysis was performed using Mann-Whitney U test. RESULTS: pHe mapping revealed that combining cTACE with prior bicarbonate infusion significantly increased tumor pHe compared to control (p = 0.0175) and cTACE alone (p = 0.0025). IHC staining revealed peritumoral accumulation of HLA-DR+ antigen-presenting cells and CD3 + T-lymphocytes in controls. cTACE-treated tumors showed reduced immune infiltration, which was restored through combination with bicarbonate. DEE-TACE with Oncozene™-DEEs induced moderate intratumoral and marked peritumoral infiltration, which was slightly reduced with bicarbonate. Addition of bicarbonate prior to LUMI™-beads enhanced peritumoral immune cell infiltration compared to LUMI™-beads alone and resulted in the strongest intratumoral immune cell infiltration across all treated groups. CONCLUSIONS: The choice of chemoembolic regimen for TACE strongly affects post-treatment TME pHe and the ability of immune cells to accumulate and infiltrate the tumor tissue. KEY POINTS: • Combining conventional transarterial chemotherapy with prior bicarbonate infusion increases the pHe towards a more physiological value (p = 0.0025). • Peritumoral infiltration and intratumoral accumulation patterns of antigen-presenting cells and T-lymphocytes after transarterial chemotherapy were dependent on the choice of the chemoembolic regimen. • Combination of intra-arterial treatment with Doxorubicin-eluting LUMI™-beads and bicarbonate infusion resulted in the strongest intratumoral presence of immune cells (positivity index of 0.47 for HLADR+-cells and 0.62 for CD3+-cells).

Assessment of the hepatic tumor extracellular matrix using elastin-specific molecular magnetic resonance imaging in an experimental rabbit cancer model.

To investigate the imaging performance of an elastin-specific molecular magnetic resonance imaging (MRI) probe with respect to the extracellular matrix (ECM) in an experimental hepatic cancer model. Twelve rabbits with hepatic VX2 tumors were examined using 3 T MRI 14, 21, and 28 days after tumor implantation for two subsequent days (gadobutrol, day 1; elastin-specific probe, day 2). The relative enhancement (RE) of segmented tumor regions (central and margin) and the peritumoral matrix was calculated using pre-contrast and delayed-phase T1w sequences. MRI measurements were correlated to histopathology and element-specific and spatially resolved mass spectrometry (MS). Mixed-model analysis was performed to assess the performance of the elastin-specific probe. In comparison to gadobutrol, the elastin probe showed significantly stronger RE, which was pronounced in the tumor margin (day 14-28: P ≤ 0.007). In addition, the elastin probe was superior in discriminating between tumor regions (χ2(4) = 65.87; P < 0.001). MRI-based measurements of the elastin probe significantly correlated with the ex vivo elastinstain (R = .84; P <0 .001) and absolute gadolinium concentrations (ICP-MS: R = .73, P <0 .01). LA-ICP-MS imaging confirmed the colocalization of the elastin-specific probe with elastic fibers. Elastin-specific molecular MRI is superior to non-specific gadolinium-based contrast agents in imaging the ECM of hepatic tumors and the peritumoral tissue.

Native T1 Mapping Magnetic Resonance Imaging as a Quantitative Biomarker for Characterization of the Extracellular Matrix in a Rabbit Hepatic Cancer Model.

To characterize the tumor extracellular matrix (ECM) using native T1 mapping magnetic resonance imaging (MRI) in an experimental hepatic cancer model, a total of 27 female New Zealand white rabbits with hepatic VX2 tumors were examined by MRI at different time points following tumor implantation (day 14, 21, 28). A steady-state precession readout single-shot MOLLI sequence was acquired in a 3 T MRI scanner in prone position using a head-neck coil. The tumors were segmented into a central, marginal, and peritumoral region in anatomical images and color-coded T1 maps. In histopathological sections, stained with H&E and Picrosirius red, the regions corresponded to central tumor necrosis and accumulation of viable cells with fibrosis in the tumor periphery. Another region of interest (ROI) was placed in healthy liver tissue. T1 times were correlated with quantitative data of collagen area staining. A two-way repeated-measures ANOVA was used to compare cohorts and tumor regions. Hepatic tumors were successfully induced in all rabbits. T1 mapping demonstrated significant differences between the different tumor regions (F(1.43,34.26) = 106.93, p < 0.001) without interaction effects between time points and regions (F(2.86,34.26) = 0.74, p = 0.53). In vivo T1 times significantly correlated with ex vivo collagen stains (area %), (center: r = 0.78, p < 0.001; margin: r = 0.84, p < 0.001; peritumoral: r = 0.73, p < 0.001). Post hoc tests using Sidak's correction revealed significant differences in T1 times between all three regions (p < 0.001). Native T1 mapping is feasible and allows the differentiation of tumor regions based on ECM composition in a longitudinal tumor study in an experimental small animal model, making it a potential quantitative biomarker of ECM remodeling and a promising technique for future treatment studies.

Idarubicin-Loaded ONCOZENE Drug-Eluting Bead Chemoembolization in a Rabbit Liver Tumor Model: Investigating Safety, Therapeutic Efficacy, and Effects on Tumor Microenvironment.

PURPOSE: To investigate toxicity, efficacy, and microenvironmental effects of idarubicin-loaded 40-µm and 100-µm drug-eluting embolic (DEE) transarterial chemoembolization in a rabbit liver tumor model. MATERIALS AND METHODS: Twelve male New Zealand White rabbits with orthotopically implanted VX2 liver tumors were assigned to DEE chemoembolization with 40-µm (n = 5) or 100-µm (n = 4) ONCOZENE microspheres or no treatment (control; n = 3). At 24-72 hours postprocedurally, multiparametric magnetic resonance (MR) imaging including dynamic contrast-enhanced (DCE), diffusion-weighted imaging (DWI), and biosensor imaging of redundant deviation in shifts (BIRDS) was performed to assess extracellular pH (pHe), followed by immediate euthanasia. Laboratory parameters and histopathologic ex vivo analysis included fluorescence confocal microscopy and immunohistochemistry. RESULTS: DCE MR imaging demonstrated a similar degree of devascularization of embolized tumors for both microsphere sizes (mean arterial enhancement, 8% ± 12 vs 36% ± 51 in controls; P = .07). Similarly, DWI showed postprocedural increases in diffusion across the entire lesion (apparent diffusion coefficient, 1.89 × 10-3 mm2/s ± 0.18 vs 2.34 × 10-3 mm2/s ± 0.18 in liver; P = .002). BIRDS demonstrated profound tumor acidosis at baseline (mean pHe, 6.79 ± 0.08 in tumor vs 7.13 ± 0.08 in liver; P = .02) and after chemoembolization (6.8 ± 0.06 in tumor vs 7.1 ± 0.04 in liver; P = .007). Laboratory and ex vivo analyses showed central tumor core penetration and greater increase in liver enzymes for 40-µm vs 100-µm microspheres. Inhibition of cell proliferation, intratumoral hypoxia, and limited idarubicin elution were equally observed with both sphere sizes. CONCLUSIONS: Noninvasive multiparametric MR imaging visualized chemoembolic effects in tumor and tumor microenvironment following DEE chemoembolization. Devascularization, increased hypoxia, coagulative necrosis, tumor acidosis, and limited idarubicin elution suggest ischemia as the predominant therapeutic mechanism. Substantial size-dependent differences indicate greater toxicity with the smaller microsphere diameter.