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Atherosclerosis is a chronic inflammatory condition of the arteries and represents the primary cause of various cardiovascular diseases. Despite ongoing progress, finding effective anti-inflammatory therapeutic strategies for atherosclerosis remains a challenge. Here, we assessed the potential of molecular magnetic resonance imaging (MRI) to visualize the effects of 01BSUR, an anti-interleukin-1β monoclonal antibody, for treating atherosclerosis in a murine model. Male apolipoprotein E-deficient mice were divided into a therapy group (01BSUR, 2 × 0.3 mg/kg subcutaneously, n = 10) and control group (no treatment, n = 10) and received a high-fat diet for eight weeks. The plaque burden was assessed using an elastin-targeted gadolinium-based contrast probe (0.2 mmol/kg intravenously) on a 3 T MRI scanner. T1-weighted imaging showed a significantly lower contrast-to-noise (CNR) ratio in the 01BSUR group (pre: 3.93042664; post: 8.4007067) compared to the control group (pre: 3.70679168; post: 13.2982156) following administration of the elastin-specific MRI probe (p < 0.05). Histological examinations demonstrated a significant reduction in plaque size (p < 0.05) and a significant decrease in plaque elastin content (p < 0.05) in the treatment group compared to control animals. This study demonstrated that 01BSUR hinders the progression of atherosclerosis in a mouse model. Using an elastin-targeted MRI probe, we could quantify these therapeutic effects in MRI., (© 2024. The Author(s).)

Prostate cancer (PCa) is a significant health problem in the male population of the Western world. Magnetic resonance elastography (MRE), an emerging medical imaging technique sensitive to mechanical properties of biological tissues, detects PCa based on abnormally high stiffness and viscosity values. Yet, the origin of these changes in tissue properties and how they correlate with histopathological markers and tumor aggressiveness are largely unknown, hindering the use of tumor biomechanical properties for establishing a noninvasive PCa staging system. To infer the contributions of extracellular matrix (ECM) components and cell motility, we investigated fresh tissue specimens from two PCa xenograft mouse models, PC3 and LNCaP, using magnetic resonance elastography (MRE), diffusion-weighted imaging (DWI), quantitative histology, and nuclear shape analysis. Increased tumor stiffness and impaired water diffusion were observed to be associated with collagen and elastin accumulation and decreased cell motility. Overall, LNCaP, while more representative of clinical PCa than PC3, accumulated fewer ECM components, induced less restriction of water diffusion, and exhibited increased cell motility, resulting in overall softer and less viscous properties. Taken together, our results suggest that prostate tumor stiffness increases with ECM accumulation and cell adhesion - characteristics that influence critical biological processes of cancer development. MRE paired with DWI provides a powerful set of imaging markers that can potentially predict prostate tumor development from benign masses to aggressive malignancies in patients. STATEMENT OF SIGNIFICANCE: Xenograft models of human prostate tumor cell lines, allowing correlation of microstructure-sensitive biophysical imaging parameters with quantitative histological methods, can be investigated to identify hallmarks of cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Constant interactions between tumor cells and the extracellular matrix (ECM) influence the progression of prostate cancer (PCa). One of the key components of the ECM are collagen fibers, since they are responsible for the tissue stiffness, growth, adhesion, proliferation, migration, invasion/metastasis, cell signaling, and immune recruitment of tumor cells. To explore this molecular marker in the content of PCa, we investigated two different tumor volumes (500 mm3 and 1000 mm3) of a xenograft mouse model of PCa with molecular magnetic resonance imaging (MRI) using a collagen-specific probe. For in vivo MRI evaluation, T1-weighted sequences before and after probe administration were analyzed. No significant signal difference between the two tumor volumes could be found. However, we detected a significant difference between the signal intensity of the peripheral tumor area and the central area of the tumor, at both 500 mm3 (p < 0.01, n = 16) and at 1000 mm3 (p < 0.01, n = 16). The results of our histologic analyses confirmed the in vivo studies: There was no significant difference in the amount of collagen between the two tumor volumes (p > 0.05), but within the tumor, higher collagen expression was observed in the peripheral area compared with the central area of the tumor. Laser ablation with inductively coupled plasma mass spectrometry further confirmed these results. The 1000 mm3 tumors contained 2.8 ± 1.0% collagen and the 500 mm3 tumors contained 3.2 ± 1.2% (n = 16). There was a strong correlation between the in vivo MRI data and the ex vivo histological data (y = −0.068x + 1.1; R2 = 0.74) (n = 16). The results of elemental analysis by inductively coupled plasma mass spectrometry supported the MRI data (y = 3.82x + 0.56; R2 = 0.79; n = 7). MRI with the collagen-specific probe in PCa enables differentiation between different tumor areas. This may help to differentiate tumor from healthy tissue, potentially identifying tumor areas with a specific tumor biology.

Prostate cancer (PCa) is one of the most common cancers in men. For detection and diagnosis of PCa, non-invasive methods, including magnetic resonance imaging (MRI), can reduce the risk potential of surgical intervention. To explore the molecular characteristics of the tumor, we investigated the applicability of ferumoxytol in PCa in a xenograft mouse model in two different tumor volumes, 500 mm3 and 1000 mm3. Macrophages play a key role in tumor progression, and they are able to internalize iron-oxide particles, such as ferumoxytol. When evaluating T2*-weighted sequences on MRI, a significant decrease of signal intensity between pre- and post-contrast images for each tumor volume (n = 14; p < 0.001) was measured. We, furthermore, observed a higher signal loss for a tumor volume of 500 mm3 than for 1000 mm3. These findings were confirmed by histological examinations and laser ablation inductively coupled plasma-mass spectrometry. The 500 mm3 tumors had 1.5% iron content (n = 14; σ = 1.1), while the 1000 mm3 tumors contained only 0.4% iron (n = 14; σ = 0.2). In vivo MRI data demonstrated a correlation with the ex vivo data (R2 = 0.75). The results of elemental analysis by inductively coupled plasma-mass spectrometry correlated strongly with the MRI data (R2 = 0.83) (n = 4). Due to its long retention time in the blood, biodegradability, and low toxicity to patients, ferumoxytol has great potential as a contrast agent for visualization PCa.

The incidence of abdominal aortic aneurysms (AAAs) has substantially increased during the last 20 years and their rupture remains the third most common cause of sudden death in the cardiovascular field after myocardial infarction and stroke. The only established clinical parameter to assess AAAs is based on the aneurysm size. Novel biomarkers are needed to improve the assessment of the risk of rupture. ADAMTS4 (A Disintegrin And Metalloproteinase with ThromboSpondin motifs 4) is a strongly upregulated proteoglycan cleaving enzyme in the unstable course of AAAs. In the screening of a one-bead-one-compound library against ADAMTS4, a low-molecular-weight cyclic peptide is discovered with favorable properties for in vivo molecular magnetic resonance imaging applications. After identification and characterization, it's potential is evaluated in an AAA mouse model. The ADAMTS4-specific probe enables the in vivo imaging-based prediction of aneurysm expansion and rupture., (© 2022. The Author(s).)

An abdominal aortic aneurysm (AAA) is a permanent dilatation of the abdominal aorta, usually accompanied by thrombus formation. The current clinical imaging modalities cannot reliably visualize the thrombus composition. Remodeling of the extracellular matrix (ECM) during AAA development leads to stiffness changes, providing a potential imaging marker. 14 apolipoprotein E-deficient mice underwent surgery for angiotensin II-loaded osmotic minipump implantation. 4 weeks post-op, 5 animals developed an AAA. The aneurysm was imaged ex vivo by microscopic multifrequency magnetic resonance elastography (µMMRE) with an in-plane resolution of 40 microns. Experiments were performed on a 7-Tesla preclinical magnetic resonance imaging scanner with drive frequencies between 1000 Hz and 1400 Hz. Shear wave speed (SWS) maps indicating stiffness were computed based on tomoelastography multifrequency inversion. As control, the aortas of 5 C57BL/6J mice were examined with the same imaging protocol. The regional variation of SWS in the thrombus ranging from 0.44 ± 0.07 to 1.20 ± 0.31 m/s was correlated fairly strong with regional histology-quantified ECM accumulation (R 2  = 0.79). Our results suggest that stiffness changes in aneurysmal thrombus reflect ECM remodeling, which is critical for AAA risk assessment. In the future, µMMRE could be used for a mechanics-based clinical characterization of AAAs in patients. STATEMENT OF SIGNIFICANCE: To our knowledge, this is the first study mapping the stiffness of abdominal aortic aneurysms with microscopic resolution of 40 µm. Our work revealed that stiffness critically changes due to extracellular matrix (ECM) remodeling in the aneurysmal thrombus. We were able to image various levels of ECM remodeling in the aneurysm reflected in distinct shear wave speed patterns with a strong correlation to regional histology-quantified ECM accumulation. The generated results are significant for the application of microscopic multifrequency magnetic resonance elastography for quantification of pathological remodeling of the ECM and may be of great interest for detailed characterization of AAAs in patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Human prostate cancer (PCa) is a type of malignancy and one of the most frequently diagnosed cancers in men. Elastin is an important component of the extracellular matrix and is involved in the structure and organization of prostate tissue. The present study examined prostate cancer in a xenograft mouse model using an elastin-specific molecular probe for magnetic resonance molecular imaging. Two different tumor sizes (500 mm 3 and 1000 mm 3 ) were compared and analyzed by MRI in vivo and histologically and analytically ex vivo. The T1-weighted sequence was used in a clinical 3-T scanner to calculate the relative contrast enhancement before and after probe administration. Our results show that the use of an elastin-specific probe enables better discrimination between tumors and surrounding healthy tissue. Furthermore, specific binding of the probe to elastin fibers was confirmed by histological examination and laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). Smaller tumors showed significantly higher signal intensity ( p > 0.001), which correlates with the higher proportion of elastin fibers in the histological evaluation than in larger tumors. A strong correlation was seen between relative enhancement (RE) and Elastica-van Gieson staining (R2 = 0.88). RE was related to inductively coupled plasma-mass spectrometry data for Gd and showed a correlation (R2 = 0.78). Thus, molecular MRI could become a novel quantitative tool for the early evaluation and detection of PCa.

Atherosclerosis is a progressive inflammatory vascular disease characterized by endothelial dysfunction and plaque burden. Extracellular matrix (ECM)-associated plasma proteins play an important role in disease development. Our magnetic resonance imaging (MRI) study investigates the feasibility of using two different molecular MRI probes for the simultaneous assessment of ECM-associated intraplaque albumin deposits caused by endothelial damage and progressive inflammation in atherosclerosis. Male apolipoprotein E-deficient ( ApoE -/- )-mice were fed a high-fat diet (HFD) for 2 or 4 months. Another ApoE -/- -group was treated with pravastatin and received a HFD for 4 months. T1- and T2*-weighted MRI was performed before and after albumin-specific MRI probe (gadofosveset) administration and a macrophage-specific contrast agent (ferumoxytol). Thereafter, laser ablation inductively coupled plasma mass spectrometry and histology were performed. With advancing atherosclerosis, albumin-based MRI signal enhancement and ferumoxytol-induced signal loss areas in T2*-weighted MRI increased. Significant correlations between contrast-to-noise-ratio (CNR) post-gadofosveset and albumin stain (R 2 = 0.78, p < 0.05), and signal loss areas in T2*-weighted MRI with Perls' Prussian blue stain (R 2 = 0.83, p < 0.05) were observed. No interference of ferumoxytol with gadofosveset enhancement was detectable. Pravastatin led to decreased inflammation and intraplaque albumin. Multi-target MRI combining ferumoxytol and gadofosveset is a promising method to improve diagnosis and treatment monitoring in atherosclerosis.

Objectives: Macrophages accumulating in the periablational rim play a pivotal role in initiating and sustaining the perifocal inflammatory reaction, which has been shown to be at least 1 of the mechanisms responsible for the systemic pro-oncogenic effects of focal hepatic radiofrequency ablation (RFA). Herein, we tested the hypothesis to use superparamagnetic iron oxide nanoparticle (SPION)-enhanced magnetic resonance imaging (MRI) for noninvasive quantification of iron-loaded macrophages in the periablational rim of VX2 tumor-bearing rabbits., Materials and Methods: Twelve VX2 tumor-bearing rabbits underwent MRI immediately after and up to 3 weeks after focal hepatic RFA. For noninvasive quantification of macrophage accumulation in the periablational rim, animals were scanned before and 24 hours after SPION injection. T2*-weighted images were analyzed and correlated with histopathological and immunohistochemical findings. Furthermore, correlations with quantitative measurements (ICP-MS [inductively coupled plasma-mass spectrometry] and LA-ICP-MS [laser ablation-ICP-MS]) were performed., Results: SPION-enhanced T2*-weighted MRI scans displayed a progressive increase in the areas of signal intensity (SI) loss within the periablational rim peaking 3 weeks after RFA. Accordingly, quantitative analysis of SI changes demonstrated a significant decline in the relative SI ratio reflecting a growing accumulation of iron-loaded macrophages in the rim. Histological analyses confirmed a progressive accumulation of iron-loaded macrophages in the periablational rim. The ICP-MS and LA-ICP-MS confirmed a progressive increase of iron concentration in the periablational rim., Conclusions: SPION-enhanced MRI enables noninvasive monitoring and quantification of ablation-induced macrophage recruitment in the periablational rim. Given the close interplay between ablation-induced perifocal inflammation and potential unwanted tumorigenic effects of RFA, SPION-enhanced MRI may serve as a valuable tool to guide and modulate adjuvant therapies after hepatic RFA., Competing Interests: Conflicts of interest and sources of funding: The authors have declared that conflict of interest exists. This study was funded by the German-Israeli Foundation of Scientific Research and Development (research grant agreement number: G-1319-201.2/2015). This study was also funded by the Deutsche Forschungsgemeinschaft (German Research Foundation)—SFB 1340/1 2018 and MA 5943/3-1/4-1/9-1., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Currently, there is no reliable nonsurgical treatment for abdominal aortic aneurysm (AAA). This study, therefore, investigates if doxycycline reduces AAA growth and the number of rupture-related deaths in a murine ApoE-/- model of AAA and whether gadofosveset trisodium-based MRI differs between animals with and without doxycycline treatment., Methods: Nine ApoE-/- mice were implanted with osmotic minipumps continuously releasing angiotensin II and treated with doxycycline (30 mg/kg/d) in parallel. After four weeks, MRI was performed at 3T with a clinical dose of the albumin-binding probe gadofosveset (0.03 mmol/kg). Results were compared with previously published wild-type control animals and with previously studied ApoE-/- animals without doxycycline treatment. Differences in mortality were also investigated between these groups., Results: In a previous study, we found that approximately 25% of angiotensin II-infused ApoE-/- mice died, whereas in the present study, only one out of 9 angiotensin II-infused and doxycycline-treated ApoE-/- mice (11.1%) died within 4 weeks. Furthermore, doxycycline-treated ApoE-/- mice showed significantly lower contrast-to-noise (CNR) values ( p =0.017) in MRI compared to ApoE-/- mice without doxycycline treatment. In vivo measurements of relative signal enhancement (CNR) correlated significantly with ex vivo measurements of albumin staining ( R 2  = 0.58). In addition, a strong visual colocalization of albumin-positive areas in the fluorescence albumin staining with gadolinium distribution in LA-ICP-MS was shown. However, no significant difference in aneurysm size was observed after doxycycline treatment., Conclusion: The present experimental in vivo study suggests that doxycycline treatment may reduce rupture-related deaths in AAA by slowing endothelial damage without reversing aneurysm growth., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Lisa C. Adams et al.)

Hepatic radiofrequency ablation (RFA) induces a drastic alteration of the biomechanical environment in the peritumoral liver tissue. The resulting increase in matrix stiffness has been shown to significantly influence carcinogenesis and cancer progression after focal RF ablation. To investigate the potential of an elastin-specific MR agent (ESMA) for the assessment of extracellular matrix (ECM) remodeling in the periablational rim following RFA in a VX2 rabbit liver tumor-model, twelve New-Zealand-White-rabbits were implanted in the left liver lobe with VX2 tumor chunks from donor animals. RFA of tumors was performed using a perfused RF needle-applicator with a mean tip temperature of 70 °C. Animals were randomized into four groups for MR imaging and scanned at four different time points following RFA (week 0 [baseline], week 1, week 2 and week 3 after RFA), followed by sacrifice and histopathological analysis. ESMA-enhanced MR imaging was used to assess ECM remodeling. Gadobutrol was used as a third-space control agent. Molecular MR imaging using an elastin-specific probe demonstrated a progressive increase in contrast-to-noise ratio (CNR) (week 3: ESMA: 28.1 ± 6.0; gadobutrol: 3.5 ± 2.0), enabling non-invasive imaging of the peritumoral zone with high spatial-resolution, and accurate assessment of elastin deposition in the periablational rim. In vivo CNR correlated with ex vivo histomorphometry (ElasticaVanGiesson-stain, y = 1.2x - 1.8, R 2  = 0.89, p < 0.05) and gadolinium concentrations at inductively coupled mass spectroscopy (ICP-MS, y = 0.04x + 1.2, R 2  = 0.95, p < 0.05). Laser-ICP-MS confirmed colocalization of elastin-specific probe with elastic fibers. Following thermal ablation, molecular imaging using an elastin-specific MR probe is feasible and provides a quantifiable biomarker for the assessment of the ablation-induced remodeling of the ECM in the periablational rim.

We aimed to retrospectively compare the perfusion parameters measured from dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) of prostate benign lesions and malignant lesions to determine the relationship between perfusion parameters. DCE-MRI was performed in patients with PCa who underwent simultaneous [ 68 Ga]Ga-prostate-specific membrane antigen (PSMA)-11 positron emission tomography (PET)/MRI. Six perfusion parameters (arrival time (AT), time to peak (TTP), wash-in slope (W-in), wash-out slope (W-out), peak enhancement intensity (PEI), and initial area under the 60-s curve (iAUC)), and a semi-quantitative parameter, standardized uptake values maximum (SUVmax) were calculated by placing regions of interest in the largest area of the lesions. The DCE-MRI parameters between prostate benign and malignant lesions were compared. The DCE-MRI parameters in both the benign and malignant lesions subgroup with SUVmax ≤ 3.0 and SUVmax > 3.0 were compared. The correlation of DCE-MRI parameters was investigated. Malignant lesions demonstrated significantly shorter TTP and higher SUVmax than did benign lesions. In the benign and malignant lesions subgroup, perfusion parameters of lesions with SUVmax ≤ 3.0 show no significant difference to those with SUVmax > 3.0. DCE-MRI perfusion parameters show a close correlation with each other. DCE-MRI parameters reflect the perfusion characteristics of intraprostatic lesions with malignant lesions, demonstrating significantly shorter TTP. There is a moderate to strong correlation between DCE-MRI parameters. Semi-quantitative analysis reflects that malignant lesions show a significantly higher SUVmax than benign lesions.

This review outlines recent preclinical and clinical advances in molecular imaging of abdominal aortic aneurysms (AAA) with a focus on molecular magnetic resonance imaging (MRI) of the extracellular matrix (ECM). In addition, developments in pharmacologic treatment of AAA targeting the ECM will be discussed and results from animal studies will be contrasted with clinical trials. Abdominal aortic aneurysm (AAA) is an often fatal disease without non-invasive pharmacologic treatment options. The ECM, with collagen type I and elastin as major components, is the key structural component of the aortic wall and is recognized as a target tissue for both initiation and the progression of AAA. Molecular imaging allows in vivo measurement and characterization of biological processes at the cellular and molecular level and sets forth to visualize molecular abnormalities at an early stage of disease, facilitating novel diagnostic and therapeutic pathways. By providing surrogate criteria for the in vivo evaluation of the effects of pharmacological therapies, molecular imaging techniques targeting the ECM can facilitate pharmacological drug development. In addition, molecular targets can also be used in theranostic approaches that have the potential for timely diagnosis and concurrent medical therapy. Recent successes in preclinical studies suggest future opportunities for clinical translation. However, further clinical studies are needed to validate the most promising molecular targets for human application.

This review summarizes recent developments regarding molecular imaging markers for magnetic resonance imaging (MRI) of prostate cancer (PCa). Currently, the clinical standard includes MR imaging using unspecific gadolinium-based contrast agents. Specific molecular probes for the diagnosis of PCa could improve the molecular characterization of the tumor in a non-invasive examination. Furthermore, molecular probes could enable targeted therapies to suppress tumor growth or reduce the tumor size.

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 (χ 2 (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.

Purpose: We aimed to evaluate the correlation between PSMA uptake and magnetic resonance imaging (MRI) PI-RADS of simultaneous [ 68 Ga]Ga-PSMA-11 PET/MRI regarding PI-RADS version 2.0 and 2.1 respectively and compared the difference between these two versions., Materials and Methods: We retrospectively analyzed a total of forty-six patients with biopsy-proven prostate cancer who underwent simultaneous [ 68 Ga]Ga-PSMA-11 PET/MRI. We classified the lesions regarding PI-RADS version 2.0 and 2.1, peripheral zone (PZ), and transitional zone (TZ), respectively. Based on regions of interest (ROI), standardized uptake values maximum (SUVmax), and corresponding lesion-to-background ratios (LBR) of SUVmax of each category, PI-RADS score 1 to 5, were measured. A comparison between PI-RADS version 2.0 and PI-RADS version 2.1 was performed., Results: A total of 215 focal prostate lesions were analyzed, including two subgroups, 125 TZ and 90 PZ. Data are reported as median and interquartile range (IQR). Regarding PI-RADS version 2.1, TZ SUVmax of each category were 1.5 (0.5, 1.9), 1.9 (0.8, 2.3), 3.3 (2.1, 4.6), 4.2 (3.1, 5.7), 7.3 (5.2, 9.7). PZ SUVmax of each category were 1.0 (0.8, 1.6), 2.5 (1.5, 3.2), 3.3 (1.9, 4.5), 4.3 (3.0, 5.4), 7.4 (5.0, 9.3). Regarding the inter-reader agreement of the overall PI-RADS assessment category, the kappa value was 0.723 for version 2.0 and 0.853 for version 2.1., Conclusion: Revisions of PI-RADS version 2.1 results in variations in lesions classification. Lesions with the PI-RADS category of 3, 4, and 5 present relatively higher intraprostatic PSMA uptake, while lesions with the PI-RADS category of 1 and 2 present relatively lower and similar uptake. Version 2.1 has higher inter-reader reproducibility than version 2.0.

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.

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease with an up to 80% mortality in case of rupture. Current biomarkers fail to account for size-independent risk of rupture. By combining the information of different molecular probes, multi-target molecular MRI holds the potential to enable individual characterization of AAA. In this experimental study, we aimed to examine the feasibility of simultaneous imaging of extracellular collagen and inflammation for size-independent prediction of risk of rupture in murine AAA. The study design consisted of: (1) A outcome-based longitudinal study with imaging performed once after one week with follow-up and death as the end-point for assessment of rupture risk. (2) A week-by-week study for the characterization of AAA development with imaging after 1, 2, 3 and 4 weeks. For both studies, the animals were administered a type 1 collagen-targeted gadolinium-based probe (surrogate marker for extracellular matrix (ECM) remodeling) and an iron oxide-based probe (surrogate marker for inflammatory activity), in one imaging session. In vivo measurements of collagen and iron oxide probes showed a significant correlation with ex vivo histology (p < 0.001) and also corresponded well to inductively-coupled plasma-mass spectrometry and laser-ablation inductively-coupled plasma mass spectrometry. Combined evaluation of collagen-related ECM remodeling and inflammatory activity was the most accurate predictor for AAA rupture (sensitivity 80%, specificity 100%, area under the curve 0.85), being superior to information from the individual probes alone. Our study supports the feasibility of a simultaneous assessment of collagen-related extracellular matrix remodeling and inflammatory activity in a murine model of AAA.

Globally, primary and secondary liver cancer is one of the most common cancer types, accounting 8.2% of deaths worldwide in 2018. One of the key strategies to improve the patient's prognosis is the early diagnosis, when liver function is still preserved. In hepatocellular carcinoma (HCC), the typical wash-in/wash-out pattern in conventional magnetic resonance imaging (MRI) reaches a sensitivity of 60% and specificity of 96-100%. However, in recent years functional MRI sequences such as hepatocellular-specific gadolinium-based dynamic-contrast enhanced MRI, diffusion-weighted imaging (DWI), and magnetic resonance spectroscopy (MRS) have been demonstrated to improve the evaluation of treatment success and thus the therapeutic decision-making and the patient's outcome. In the preclinical research setting, the VX2 liver rabbit tumor, which once originated from a virus-induced anaplastic squamous cell carcinoma, has played a longstanding role in experimental interventional oncology. Especially the high tumor vascularity allows assessing the treatment response of locoregional interventions such as radiofrequency ablation (RFA) and transcatheter arterial embolization (TACE). Functional MRI has been used to monitor the tumor growth and viability following interventional treatment. Besides promising results, a comprehensive overview of functional MRI sequences used so far in different treatment setting is lacking, thus lowering the comparability of study results. This review offers a comprehensive overview of study protocols, results, and limitations of quantitative MRI sequences applied to evaluate the treatment outcome of VX2 hepatic tumor models, thus generating a unique basis for future MRI studies and potential translation into the clinical setting. Level of Evidence: 2 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2019. J. Magn. Reson. Imaging 2020;52:668-685., (© 2019 International Society for Magnetic Resonance in Medicine.)

Abdominal aortic aneurysms (AAAs) are currently one of the leading causes of death in developed countries. Inflammation is crucial in the disease progression, having a substantial impact on various determinants in AAAs development. Magnetic particle imaging (MPI) is an innovative imaging modality, enabling the highly sensitive detection of magnetic nanoparticles (MNPs), suitable as surrogate marker for molecular targeting of vascular inflammation. For this study, Apolipoprotein E-deficient-mice underwent surgical implantation of osmotic minipumps with constant Angiotensin II infusion. After 3 and 4 weeks respectively, in-vivo-magnetic resonance imaging (MRI), ex-vivo-MPI and ex-vivo-magnetic particle spectroscopy (MPS) were performed. The results were validated by histological analysis, immunohistology and laser ablation-inductively coupled plasma-mass spectrometry. MR-angiography enabled the visualization of aneurysmal development and dilatation in the experimental group. A close correlation (R = 0.87) with histological area assessment was measured. Ex-vivo-MPS revealed abundant iron deposits in AAA samples and ex-vivo histopathology measurements were in good agreement (R = 0.76). Ex-vivo-MPI and MPS results correlated greatly (R = 0.99). CD68-immunohistology stain and Perls'-Prussian-Blue-stain confirmed the colocalization of macrophages and MNPs. This study demonstrates the feasibility of ex-vivo-MPI for detecting inflammation in AAA. The quantitative ability for mapping MNPs establishes MPI as a promising tool for monitoring inflammatory progression in AAA in an experimental setting.

68 Ga-DOTATOC PET/MRI combines the advantages of PET in the acquisition of metabolic-functional information with the high soft-tissue contrast of MRI. SUVs in tumors have been suggested to be a measure of somatostatin receptor expression. A challenge with receptor ligands is that the distribution volume is confined to tissues with tracer uptake, potentially limiting SUV quantification. In this study, various functional 3-dimensional SUV apparent diffusion coefficient (ADC) parameters and arterial tumor enhancement were tested for ability to characterize gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). Methods: For this single-center, cross-sectional study, 22 patients with 24 histologically confirmed GEP NET lesions (15 men and 7 women; median age, 61 y; range, 43-81 y) who underwent hybrid 68 Ga-DOTA PET/MRI at 3 T between January 2017 and July 2019 met the eligibility criteria. SUV, tumor-to-background ratio, total functional tumor volume, and mean and minimum ADC were measured on the basis of volumes of interest and examined with receiver-operating-characteristic analysis to determine cutoffs for differentiation between low- and intermediate-grade GEP NETs. The Spearman rank correlation coefficient was used to assess correlations between functional imaging parameters. Results: The ratio of PET-derived SUV mean and diffusion-weighted imaging-derived minimum ADC was introduced as a combined variable to predict tumor grade, outperforming single predictors. On the basis of a threshold ratio of 0.03, tumors could be classified as grade 2 with a sensitivity of 86% and a specificity of 100%. SUV and functional ADCs, as well as arterial contrast enhancement parameters, showed nonsignificant and mostly negligible correlations. Conclusion: Because receptor density and tumor cellularity appear to be independent, potentially complementary phenomena, the combined ratio of PET/MRI and SUV mean /ADC min may be used as a novel biomarker allowing differentiation between grade 1 and grade 2 GEP NETs., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Abdominal aortic aneurysm (AAA) remains a fatal disease. Its development encompasses a complex interplay between hemodynamic stimuli on and changes in the arterial wall. Currently available biomarkers fail to predict the risk of AAA rupture independent of aneurysm size. Therefore, novel biomarkers for AAA characterization are needed. In this study, we used a mouse model of AAA to investigate the potential of magnetic resonance imaging (MRI) with an albumin-binding probe to assess changes in vascular permeability at different stages of aneurysm growth. Two imaging studies were performed: a longitudinal study with follow-up and death as endpoint to predict rupture risk and a week-by-week study to characterize AAA development. AAAs, which eventually ruptured, demonstrated a significantly higher in vivo MR signal enhancement from the albumin-binding probe (p = 0.047) and a smaller nonenhancing thrombus area compared to intact AAAs (p = 0.001). The ratio of albumin-binding-probe enhancement of the aneurysm wall to size of nonenhancing-thrombus-area predicted AAA rupture with high sensitivity/specificity (100%/86%). More advanced aneurysms with higher vascular permeability demonstrated an increased uptake of the albumin-binding-probe. These results indicate that MRI with an albumin-binding probe may enable noninvasive assessment of vascular permeability in murine AAAs and prediction of rupture risk.

Background: Molecular-MRI is a promising imaging modality for the assessment of abdominal aortic aneurysms (AAAs). Interleukin-1β (IL-1β) represents a new therapeutic tool for AAA-treatment, since pro-inflammatory cytokines are key-mediators of inflammation. This study investigates the potential of molecular-MRI to evaluate therapeutic effects of an anti-IL-1β-therapy on AAA-formation in a mouse-model., Methods: Osmotic-minipumps were implanted in apolipoprotein-deficient-mice (N = 27). One group (Ang-II+01BSUR group, n = 9) was infused with angiotensin-II (Ang-II) for 4 weeks and received an anti-murine IL-1β-antibody (01BSUR) 3 times. One group (Ang-II-group, n = 9) was infused with Ang-II for 4 weeks but received no treatment. Control-group (n = 9) was infused with saline and received no treatment. MR-imaging was performed using an elastin-specific gadolinium-based-probe (0.2 mmol/kg)., Results: Mice of the Ang-II+01BSUR-group showed a lower aortic-diameter compared to mice of the Ang-II-group and control mice (p < 0.05). Using the elastin-specific-probe, a significant decrease in elastin-destruction was observed in mice of the Ang-II+01BSUR-group. In vivo MR-measurements correlated well with histopathology (y = 0.34x-13.81, R 2 = 0.84, p < 0.05), ICP-MS (y = 0.02x+2.39; R 2 = 0.81, p < 0.05) and LA-ICP-MS. Immunofluorescence and western-blotting confirmed a reduced IL-1β-expression., Conclusions: Molecular-MRI enables the early visualization and quantification of the anti-inflammatory-effects of an IL-1β-inhibitor in a mouse-model of AAAs. Responders and non-responders could be identified early after the initiation of the therapy using molecular-MRI.

Molecular MRI is a promising in-vivo modality to detect and quantify morphological and molecular vessel-wall changes in atherosclerosis. The combination of different molecular biomarkers may improve the risk stratification of patients. This study aimed to investigate the feasibility of simultaneous visualization and quantification of plaque-burden and inflammatory activity by dual-probe molecular MRI in a mouse-model of progressive atherosclerosis and in response-to-therapy. Homozygous apolipoprotein E knockout mice (ApoE -/- ) were fed a high-fat-diet (HFD) for up to four-months prior to MRI of the brachiocephalic-artery. To assess response-to-therapy, a statin was administered for the same duration. MR imaging was performed before and after administration of an elastin-specific gadolinium-based and a macrophage-specific iron-oxide-based probe. Following in-vivo MRI, samples were analyzed using histology, immunohistochemistry, inductively-coupled-mass-spectrometry and laser-inductively-coupled-mass-spectrometry. In atherosclerotic-plaques, intraplaque expression of elastic-fibers and inflammatory activity were not directly linked. While the elastin-specific probe demonstrated the highest accumulation in advanced atherosclerotic-plaques after four-months of HFD, the iron-oxide-based probe showed highest accumulation in early atherosclerotic-plaques after two-months of HFD. In-vivo measurements for the elastin and iron-oxide-probe were in good agreement with ex-vivo histopathology (Elastica-van-Giesson stain: y = 298.2 + 5.8, R 2  = 0.83, p < 0.05; Perls' Prussian-blue-stain: y = 834.1 + 0.67, R 2  = 0.88, p < 0.05). Contrast-to-noise-ratio (CNR) measurements of the elastin probe were in good agreement with ICP-MS (y = 0.11x-11.3, R² = 0.73, p < 0.05). Late stage atherosclerotic-plaques displayed the strongest increase in both CNR and gadolinium concentration (p < 0.05). The gadolinium probe did not affect the visualization of the iron-oxide-probe and vice versa. This study demonstrates the feasibility of simultaneous assessment of plaque-burden and inflammatory activity by dual-probe molecular MRI of progressive atherosclerosis. The in-vivo detection and quantification of different MR biomarkers in a single scan could be useful to improve characterization of atherosclerotic-lesions.

Background: Magnetic resonance angiography (MRA) represents a clinical reference standard for the in vivo assessment of the vasculature. In this study, the potential of non-contrast-enhanced and contrast-enhanced angiography of the head/neck vasculature in mice on a clinical MR imaging system was tested., Methods: All in vivo magnetic resonance imaging was performed with a 3T clinical system (Siemens). Non-contrast-enhanced (time-of-flight, TOF) and contrast-enhanced angiography (gadofosveset-trisodium, GdT) were performed in C57BL/6J mouse strain. Lumen-to-muscle ratios (LMRs) and area measurements were assessed. Histology was performed as reference standard of all relevant vascular structures., Results: A close correlation between TOF ( R 2  = 0.79; p < 0.05) and contrast-enhanced (GdT) angiography ( R 2  = 0.92; p < 0.05) with histological area measurements was found. LMRs were comparable between both sequences. Regarding interobserver reproducibility, contrast-enhanced (GdT) angiography yielded a smaller 95% confidence interval and a closer interreader correlation compared to non-contrast-enhanced (TOF) measurements (-0.73-0.89; R 2  = 0.81 vs. -0.55-0.56; R 2  = 0.94)., Conclusion: This study demonstrates that non-contrast-enhanced and contrast-enhanced angiographies of the head/neck vasculature of small animals can reliably performed on a clinical 3T MR scanner. Contrast-enhanced angiography enables the visualization of vascular structures with higher intravascular contrast and higher reproducibility.

Background: Molecular magnetic resonance imaging is a promising modality for the characterization of abdominal aortic aneurysms (AAAs). The combination of different molecular imaging biomarkers may improve the assessment of the risk of rupture. This study investigates the feasibility of imaging inflammatory activity and extracellular matrix degradation by concurrent dual-probe molecular magnetic resonance imaging in an AAA mouse model., Methods: Osmotic minipumps with a continuous infusion of Ang II (angiotensin II; 1000 ng/[kg·min]) to induce AAAs were implanted in apolipoprotein-deficient mice (N=58). Animals were assigned to 2 groups. In group 1 (longitudinal group, n=13), imaging was performed once after 1 week with a clinical dose of a macrophage-specific iron oxide-based probe (ferumoxytol, 4 mgFe/kg, surrogate marker for inflammatory activity) and an elastin-specific gadolinium-based probe (0.2 mmol/kg, surrogate marker for extracellular matrix degradation). Animals were then monitored with death as end point. In group 2 (week-by-week-group), imaging with both probes was performed after 1, 2, 3, and 4 weeks (n=9 per group). Both probes were evaluated in 1 magnetic resonance session., Results: The combined assessment of inflammatory activity and extracellular matrix degradation was the strongest predictor of AAA rupture (sensitivity 100%; specificity 89%; area under the curve, 0.99). Information from each single probe alone resulted in lower predictive accuracy. In vivo measurements for the elastin- and iron oxide-probe were in good agreement with ex vivo histopathology (Prussian blue-stain: R 2 =0.96, P<0.001; Elastica van Giesson stain: R 2 =0.79, P<0.001). Contrast-to-noise ratio measurements for the iron oxide and elastin-probe were in good agreement with inductively coupled mass spectroscopy ( R 2 =0.88, R 2 =0.75, P<0.001) and laser ablation coupled to inductively coupled plasma-mass spectrometry., Conclusions: This study demonstrates the potential of the concurrent assessment of inflammatory activity and extracellular matrix degradation by dual-probe molecular magnetic resonance imaging in an AAA mouse model. Based on the combined information from both molecular probes, the rupture of AAAs could reliably be predicted.

Objectives: The aim of this study was to test the potential of a new elastin-specific molecular agent for the performance of contrast-enhanced first-pass and 3D magnetic resonance angiography (MRA), compared to a clinically used extravascular contrast agent (gadobutrol) and based on clinical MR sequences., Materials and Methods: Eight C57BL/6J mice (BL6, male, aged 10 weeks) underwent a contrast-enhanced first-pass and 3D MR angiography (MRA) of the aorta and its main branches. All examinations were on a clinical 3 Tesla MR system (Siemens Healthcare, Erlangen, Germany). The clinical dose of 0.1 mmol/kg was administered in both probes. First, a time-resolved MRA (TWIST) was acquired during the first-pass to assess the arrival and washout of the contrast agent bolus. Subsequently, a high-resolution 3D MRA sequence (3D T1 FLASH) was acquired. Signal-to-noise ratios (SNRs) and contrast-to-noise ratios (CNRs) were calculated for all sequences., Results: The elastin-specific MR probe and the extravascular imaging agent (gadobutrol) enable high-quality MR angiograms in all animals. During the first-pass, the probes demonstrated a comparable peak enhancement (300.6 ± 32.9 vs. 288.5 ± 33.1, p > 0.05). Following the bolus phase, both agents showed a comparable intravascular enhancement (SNR: 106.7 ± 11 vs. 102.3 ± 5.3; CNR 64.5 ± 7.4 vs. 61.1 ± 7.2, p > 0.05). Both agents resulted in a high image quality with no statistical difference ( p > 0.05)., Conclusion: The novel elastin-specific molecular probe enables the performance of first-pass and late 3D MR angiography with an intravascular contrast enhancement and image quality comparable to a clinically used extravascular contrast agent.

Background: The incidence of abdominal aortic aneurysms (AAAs) will significantly increase during the next decade. Novel biomarkers, besides diameter, are needed for a better characterization of aneurysms and the estimation of the risk of rupture. Fibrin is a key protein in the formation of focal hematoma associated with the dissection of the aortic wall and the development of larger thrombi during the progression of AAAs. This study evaluated the potential of a fibrin-specific magnetic resonance (MR) probe for the in vivo characterization of the different stages of AAAs., Methods and Results: AAAs spontaneously developed in ApoE -/- mice following the infusion of angiotensin-II (Ang-II, 1 μg/kg -1 ·per minute). An established fibrin-specific molecular MR probe (EP2104R, 10 μmol/kg -1 ) was administered after 1 to 4 weeks following Ang-II infusion (n=8 per group). All imaging experiments were performed on a clinical 3T Achieva MR system with a microscopy coil (Philips Healthcare, Netherlands). The development of AAA-associated fibrin-rich hematoma and thrombi was assessed. The high signal generated by the fibrin probe enabled high-resolution MR imaging for an accurate assessment and quantification of the relative fibrin composition of focal hematoma and thrombi. Contrast-to-noise-ratios (CNRs) and R1-relaxation rates following the administration of the fibrin probe were in good agreement with ex vivo immunohistomorphometry ( R 2 =0.83 and 0.85) and gadolinium concentrations determined by inductively coupled plasma mass spectroscopy ( R 2 =0.78 and 0.72)., Conclusions: The fibrin-specific molecular MR probe allowed the delineation and quantification of changes in fibrin content in early and advanced AAAs. Fibrin MRI could provide a novel in vivo biomarker to improve the risk stratification of patients with aortic aneurysms., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

The development of abdominal aortic aneurysm (AAA) associated thrombi plays an important role during the onset and progression of AAAs. The aim of this study was to evaluate the potential of high-frequency ultrasound for characterization of AAA associated thrombi in an apolipoprotein-E-deficient mouse-model. Ultrasound measurements were performed using a high-resolution ultrasound system (Vevo770, FUJIFILM VisualSonics, Inc., Toronto, ON, Canada) with a 30 MHz linear-array transducer (RMV707 B). Magnetic resonance imaging with a 3 Tesla scanner (Achieva MR system, Philips Healthcare, Best, The Netherlands) and a single-loop microscopy coil was performed as a reference standard. All stages of aneurysm development were evaluated by histologic analyses. The "signal-thrombus-matrix" to "signal-blood" ratio on high-frequency ultrasound measurements showed a strong correlation (R 2  = 0.81, p <0.05) with the state of extracellular matrix remodeling. Furthermore, size measurements derived from the high-frequency ultrasound correlated well with magnetic resonance imaging and histology. This study demonstrated that high-frequency ultrasound enables the reliable in vivo quantification of extracellular matrix remodeling at various stages of thrombus development, based on the thrombus echogenicity., (Copyright © 2017 World Federation for Ultrasound in Medicine and Biology. Published by Elsevier Inc. All rights reserved.)

Background: MR-angiography currently represents one of the clinical reference-standards for the assessment of aortic-dimensions. For experimental research in mice, dedicated preclinical high-field MRI scanners are used in most studies. This type of MRI scanner is not available in most institutions. The aim of this study was to evaluate the potential of MR-angiography performed on a clinical MR scanner for the assessment of aortic aneurysms in an experimental mouse model, compared to a preclinical high-resolution ultrasound imaging system and histopathology., Methods: All in vivo MR imaging was performed with a clinical 3T MRI system (Philips Achieva) equipped with a clinical gradient system in combination with a single-loop surface-coil (47 mm). All MR sequences were based on clinically used sequences. For ultrasound, a dedicated preclinical high-resolution system (30 MHz linear transducer, Vevo770, VisualSonics) was used. All imaging was performed with an ApoE knockout mouse-model for aortic aneurysms. Histopathology was performed as reference-standard at all stages of aneurysm development., Results: MR-angiography on a clinical 3T system enabled the clear visualization of the aortic lumen and aneurysmal dilation at different stages of aneurysm development. A close correlation (R2 = 0.98; p < 0.001) with histological area measurements was found. Additionally, a good agreement between MR and ultrasound area measurements in systole (R2 = 0.91; p < 0.001) and diastole (R2 = 0.94; p < 0.001) were measured. Regarding interobserver reproducibility, MRI measurements yielded a smaller 95% confidence interval and a closer interreader correlation compared to ultrasound measurements (-0.37-0.46; R2 = 0.97 vs. -0.78-0.88; R2 = 0.87)., Conclusion: This study demonstrates that MR-angiography, performed on a clinical 3T MR scanner, enables the reliable detection and quantification of the aortic dilatation at different stages of aneurysm development in an experimental mouse model.

This review summarizes the current status of molecular imaging of the extracellular matrix (ECM) in the context of atherosclerosis. Apart from cellular components, the ECM of the atherosclerotic plaque plays a relevant role during the initiation of atherosclerosis and its' subsequent progression. Important structural and signaling components of the ECM include elastin, collagen and fibrin. However, the ECM not only plays a structural role in the arterial wall but also interacts with different cell types and has important biological signaling functions. Molecular imaging of the ECM has emerged as a new diagnostic tool to characterize biological aspects of atherosclerotic plaques, which cannot be characterized by current clinically established imaging techniques, such as X-ray angiography. Different types of molecular probes can be detected in vivo by imaging modalities such as magnetic resonance imaging (MRI), positron emission tomography (PET) and single photon emission computed tomography (SPECT). The modality specific signaling component of the molecular probe provides information about its spatial location and local concentration. The successful introduction of molecular imaging into clinical practice and guidelines could open new pathways for an earlier detection of disease processes and a better understanding of the disease state on a biological level. Quantitative in vivo molecular parameters could also contribute to the development and evaluation of novel cardiovascular therapeutic interventions and the assessment of response to treatment., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Abdominal aortic aneurysms (AAAs) represent a vascular disease with severe complications. AAAs are currently the overall 10th leading cause of death in western countries and their incidence is rising. Although different diagnostic techniques are currently available in clinical practice, including ultrasound (US), magnetic resonance imaging (MRI), and computed tomography (CT), imaging-based prediction of life-threatening complications such as aneurysm-rupture remains challenging. Molecular imaging provides a novel diagnostic approach for in vivo visualization of biological processes and pathological alterations at a cellular and molecular level. Its overall aim is to improve our understanding of disease pathogenesis and to facilitate novel diagnostic pathways. This review outlines recent preclinical and clinical developments in molecular MRI, positron emission tomography (PET), and single-photon emission computed tomography (SPECT) for imaging of AAAs., (Copyright © 2017 Elsevier Ltd. All rights reserved.)