Detection of recurrent hepatocellular carcinoma on post-operative surveillance: comparison of MDCT and gadoxetic acid-enhanced MRI

Objective

To compare the accuracy of multidetector computed tomography (MDCT) and gadoxetic acid-enhanced magnetic resonance imaging (MRI) for the detection of intrahepatic tumor recurrence after curative resection of hepatocellular carcinoma (HCC).

Materials and methods

Fifty-six patients who underwent MDCT and gadoxetic acid-enhanced MRI for postoperative surveillance after resection of HCC were retrospectively analyzed; 26 patients had a recurrence (36 lesions) and 30 patients did not. Recurrent HCCs were confirmed by histological examinations in two, typical dynamic imaging findings on CT and/or MRI in 28, and by demonstration of growth or tumor staining on angiography on six. Two reviewers graded the confidence for the presence of recurrence on CT and MRI, using a five-point scale. The jackknife free-response receiver operating characteristic method was used to compare diagnostic performance. The accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated.

Results

For 36 recurrent lesions, the figure of merit was significantly higher for MRI than MDCT for detecting recurrence for both reviewers (p < 0.005 for both reviewers). In lesion-by-lesion analysis, the sensitivity was significantly higher on MRI (100% for reviewer 1 and 97% for reviewer 2) than on MDCT (44.4% and 66.6%) for both reviewers (p < 0.005 for both reviewers). Also in patient-by-patient analysis, sensitivity was significantly higher on MRI (100% and 96.1%) than on MDCT (57.6% and 76.9%) for both reviewers (p < 0.05 for both reviewers).

Conclusion

Gadoxetic acid-enhanced MRI is superior to MDCT for detecting intrahepatic recurrence after curative resection of HCC.     

Dynamic Measurement of Tumor Vascular Permeability and Perfusion using a Hybrid System for Simultaneous Magnetic Resonance and Fluorescence Imaging

Purpose

Assessing tumor vascular features including permeability and perfusion is essential for diagnostic and therapeutic purposes. The aim of this study was to compare fluorescence and magnetic resonance imaging (MRI)-based vascular readouts in subcutaneously implanted tumors in mice by simultaneous dynamic measurement of tracer uptake using a hybrid fluorescence molecular tomography (FMT)/MRI system.

Procedure

Vascular permeability was measured using a mixture of extravascular imaging agents, GdDOTA and the dye Cy5.5, and perfusion using a mixture of intravascular agents, Endorem and a fluorescent probe (Angiosense). Dynamic fluorescence reflectance imaging (dFRI) was integrated into the hybrid system for high temporal resolution.

Results

Excellent correspondence between uptake curves of Cy5.5/GdDOTA and Endorem/Angiosense has been found with correlation coefficients R?>?0.98. The two modalities revealed good agreement regarding permeability coefficients and centers-of-gravity of the imaging agent distribution.

Conclusion

The FMT/dFRI protocol presented is able to accurately map physiological processes and poses an attractive alternative to MRI for characterizing tumor neoangiogenesis.

     

Assessment and comparison of magnetic nanoparticles as MRI contrast agents in a rodent model of human hepatocellular carcinoma

The purpose of this study was to synthesize, characterize and tailor the surface properties of magnetic nanoparticles with biocompatible copolymer coatings and to evaluate the efficiency of the resulting nanoconjugates as magnetic resonance imaging (MRI) contrast agents for liver imaging. Magnetic nanoparticles with core diameters of 10 and 30 nm were synthesized by pyrolysis and were subsequently coated with a copolymer containing either carboxyl (SHP) or methoxy groups as termini. All four formulas, and ferumoxides (Feridex I.V.®), were individually injected intravenously into separate, normal Balb/C mice (at 2.5, 1.0 and 0.56 mg Fe kg^?1), and the animals underwent T₂‐weighted MRI at multiple time points post injection (p.i.) to evaluate the hepatic uptake and clearance. Furthermore, we compared the abilities of the new formulas and Feridex to detect tumors in an orthotropic Huh7 tumor model. Transmission electron microscopy (TEM) revealed a narrow size distribution of both the 10 and 30 nm nanoparticles, in contrast to a wide size distribution of Feridex. MTT, apoptosis and cyclin/DNA flow cytometry assays showed that the polymer coated nanoparticles had no adverse effect on cell growth. Among all the tested formulas, including Feridex, SHP‐30 showed the highest macrophage uptake at the in vitro level. In vivo MRI studies on normal mice confirmed the superiority of SHP‐30 in inducing hypointensities in the liver tissue, especially at clinical dose (0.56 mg Fe kg^?1) and 3 T field. SHP‐30 showed better contrast‐to‐noise ratio than Feridex on the orthotropic Huh7 tumor model. SHP‐30 was found to be an efficient contrast agent for liver MR imaging. The success of this study suggests that, by improving the synthetic approach and by tuning the surface properties of IONPs, one can arrive at better formulas than Feridex for clinical practice. Copyright © 2012 John Wiley & Sons, Ltd.     

携HMME-Gd液态氟碳纳米粒造影剂的制备及体外双模态成像研究

目的 制备携带血卟啉单甲醚-钆(HMME-Gd)的液态氟碳纳米粒(HMME-Gd-PFPNPs),观察体外US/MRI的成像效果。方法 以磷脂、胆固醇、HMME-Gd和全氟戊烷(PFP)为原料,用薄膜水化法和乳化法制备脂质体纳米粒HMME-Gd-PFPNPs。倒置光学显微镜、透射电子显微镜及激光共聚焦显微镜检测其基本表征;粒径分析仪分析粒径及表面电位;紫外分光光度计分析HMME-Gd的包封率;观察HMME-Gd-PFPNPs体外US/MRI成像的效果。结果 成功制备HMME-Gd-PFPNPs,光镜下为形态规则、大小均一的球形,电镜下为黑色的球形结构。HMME-Gd-PFPNPs平均粒径为(250.27 ± 11.9)nm,电位为(-26.17 ± 0.45)mV,HMME-Gd的包封率为(84.7 ± 0.35)%。在低强度聚焦超声辐照下,体外US成像信号显著增强,与LIFU激发强度成正相关。随HMME-Gd-PFPNPs浓度增加,体外MRI成像效果显著增强。结论 成功制备了携带HMME-Gd的液态氟碳纳米粒,可用于体外US/MRI双模态成像。     

In vitro and in vivo targeting of hollow gold nanoshells directed at epidermal growth factor receptor for photothermal ablation therapy

Laser-induced phototherapy is a new therapeutic use of electromagnetic radiation for cancer treatment. The use of targeted plasmonic gold nanoparticles can reduce the laser energy necessary for selective tumor cell destruction. However, the ability for targeted delivery of the currently used gold nanoparticles to tumor cells is limited. Here, we describe a new class of molecular specific photothermal coupling agents based on hollow gold nanoshells (HAuNS; average diameter, approximately 30 nm) covalently attached to monoclonal antibody directed at epidermal growth factor receptor (EGFR). The resulting anti-EGFR-HAuNS exhibited excellent colloidal stability and efficient photothermal effect in the near-infrared region. EGFR-mediated selective uptake of anti-EGFR-HAuNS in EGFR-positive A431 tumor cells but not IgG-HAuNS control was shown in vitro by imaging scattered light from the nanoshells. Irradiation of A431 cells treated with anti-EGFR-HAuNS with near-infrared laser resulted in selective destruction of these cells. In contrast, cells treated with anti-EGFR-HAuNS alone, laser alone, or IgG-HAuNS plus laser did not show observable effect on cell viability. Using 111In-labeled HAuNS, we showed that anti-EGFR-HAuNS could be delivered to EGFR-positive tumors at 6.8% ID/g, and the microscopic image of excised tumor with scattering signal from nanoshells confirmed preferential delivery to A431 tumor of anti-EGFR-HAuNS compared with IgG-HAuNS. The absence of silica core, the relatively small particle size and high tumor uptake, and the absence of cytotoxic surfactant required to stabilize other gold nanoparticles suggest that immuno-HAuNS have the potential to extend to in vivo molecular therapy.     

Preparation and characterization of peptide modified ultrasmall superparamagnetic iron oxides used as tumor targeting MRI contrast agent

As desirable contrast agents for magnetic resonance imaging (MRI), ultrasmall superparamagnetic iron oxides (USPIOs) are required to exhibit both low cytotoxicity and specific targetability besides superparamagnetism to achieve better imaging contrast at lower dose, and cladding with biocompatible polymers and modification with targeting ligands are considered to be the most effective strategies. In this study, novel dextran wrapped and peptide WSGPGVWGASVK (peptide-WSG) grafted USPIOs were meticulously prepared and systematically characterized. Firstly, dextran (Dex) cladded USPIOs (USPIOs@Dex) were synthesized with a well-designed co-precipitation procedure in which the biocompatible dextran played dual roles of grain inhibitor and cladding agent. After that, sodium citrate was applied to carboxylize the hydroxyls of the dextran molecules via an esterification reaction, and then tumor targeting peptide-WSG was grafted to the carboxyl groups by the EDC method. The XRD, TEM, and FTIR results showed that inverse spinel structure Fe₃O₄ crystallites were nucleated and grown in aqueous solution, and the catenulate dextran molecules gradually bound on their surface, meanwhile the growth of grains was inhibited. The size of original crystallite grains was about 7 nm, but the mean size of USPIOs@Dex aggregates was 165.20 nm. After surface modification by sodium citrate and peptide-WSG with ultrasonic agitation, the size of the USPIOs@Dex-WSG aggregates was smaller (66.06 nm) because the hydrophilicity was improved, so USPIOs@Dex-WSG could evade being eliminated by RES more easily, and prolong residence time in blood circulation. The VSM and T₂-weighted MRI results showed that USPIOs@Dex-WSG were superparamagnetic with a saturation magnetization of 44.65 emu g⁻¹, and with high transverse relaxivity as the R₂ relaxivity coefficient value was 229.70 mM⁻¹ s⁻¹. The results of MTT assays and the Prussian blue staining in vitro revealed that USPIOs@Dex-WSG exhibited nontoxicity for normal cells such as L929 and HUVECs, and were specifically targeted to the SKOV-3 cells. Thus, the novel dextran wrapped and WSG-peptide grafted USPIOs have potential to be applied as tumor active targeting contrast agents for MRI.

As desirable contrast agents for magnetic resonance imaging (MRI), ultrasmall superparamagnetic iron oxides (USPIOs) modified with targeting ligands are considered to be the most effective strategies to achieve better imaging contrast at lower dose.     

Contrast-Enhanced Ultrasound for Monitoring Non-surgical Treatments of Uterine Fibroids: A Systematic Review

Non-surgical treatment options for uterine fibroids are uterine artery embolization (UAE), high-intensity focused ultrasound ablation (HIFUA), and percutaneous microwave ablation (PMWA). Magnetic resonance imaging (MRI) is the reference standard imaging method before and after these procedures. Contrast-enhanced ultrasound (CEUS) has been studied as an alternative to MRI for evaluating the fibroids’ characteristics and responses to non-surgical treatments. PubMed, Ovid MEDLINE and Scopus databases were searched for literature published from January 2000 through June 7, 2020, that investigated the application of CEUS as an adjunct to monitor UAE, HIFUA or PMWA in human uterine fibroid treatments. Two independent reviewers analyzed 128 publications, out of which 17 were included. Based on this systematic review, CEUS provides detailed data about fibroid volume and vascularization prior, during and post UAE, and it helps determine the endpoint of the procedure. HIFUA with intra-procedural CEUS has faster volume shrinkage over a shorter time period with less needed energy and provides early detection of residual tissue after HIFUA. CEUS and contrast-enhanced MRI have sufficient agreement to be used interchangeably in the clinic to evaluate the therapeutic effect of PMWA and HIFUA on fibroids.     

Bimodal Perfluorocarbon Nanoemulsions for Nasopharyngeal Carcinoma Targeting

Purpose

The aim of this study was to perform the detection of folate receptor (FR)-positive tumors with a bimodal imaging contrast agent, a perfluorocarbon (PFC)/rhodamine nanoemulsion, providing both ¹⁹F-based magnetic resonance imaging (MRI) and fluorescence imaging capabilities.

Procedures

The PFC/rhodamine nanoemulsion was further infused with phospholipid-anchored folate to improve the ability to target FR-expressing tumors. The preferential accumulation of the FR-targeted bimodal nanoemulsion in FR-positive tumor sites was monitored by both ¹⁹F-MRI and optical imaging.

Results

The FR-targeted PFC nanoemulsion had no significant effect on cell viability, and the size and fluorescence signal of PFC nanoemulsion were very stable. These nanoprobes were successfully delivered into FR-positive tumor xenograft models and showed significantly enhanced signal intensities of ¹⁹F-MRI and fluorescence imaging in the tumor area.

Conclusions

The folate-PFC/rhodamine nanoemulsion has a great potential to serve as a useful optical and ¹⁹F-MRI agent for the diagnosis and targeting of FR-positive tumor.     

Optimized time‐resolved imaging of contrast kinetics (TRICKS) in dynamic contrast‐enhanced MRI after peptide receptor radionuclide therapy in small animal tumor models

Anti‐tumor efficacy of targeted peptide‐receptor radionuclide therapy (PRRT) relies on several factors, including functional tumor vasculature. Little is known about the effect of PRRT on tumor vasculature. With dynamic contrast‐enhanced (DCE‐) MRI, functional vasculature is imaged and quantified using contrast agents. In small animals DCE‐MRI is a challenging application. We optimized a clinical sequence for fast hemodynamic acquisitions, time‐resolved imaging of contrast kinetics (TRICKS), to obtain DCE‐MRI images at both high spatial and high temporal resolution in mice and rats. Using TRICKS, functional vasculature was measured prior to PRRT and longitudinally to investigate the effect of treatment on tumor vascular characteristics. Nude mice bearing H69 tumor xenografts and rats bearing syngeneic CA20948 tumors were used to study perfusion following PRRT administration with ¹⁷⁷lutetium octreotate. Both semi‐quantitative and quantitative parameters were calculated. Treatment efficacy was measured by tumor‐size reduction. Optimized TRICKS enabled MRI at 0.032 mm³ voxel size with a temporal resolution of less than 5 s and large volume coverage, a substantial improvement over routine pre‐clinical DCE‐MRI studies. Tumor response to therapy was reflected in changes in tumor perfusion/permeability parameters. The H69 tumor model showed pronounced changes in DCE‐derived parameters following PRRT. The rat CA20948 tumor model showed more heterogeneity in both treatment outcome and perfusion parameters. TRICKS enabled the acquisition of DCE‐MRI at both high temporal resolution (T_res) and spatial resolutions relevant for small animal tumor models. With the high T_res enabled by TRICKS, accurate pharmacokinetic data modeling was feasible. DCE‐MRI parameters revealed changes over time and showed a clear relationship between tumor size and K_trans. Copyright © 2015 John Wiley & Sons, Ltd.     

颈静脉孔区神经鞘瘤的CT和MRI诊断

目的：探讨CT和MRI对颈静脉孔区神经鞘瘤的诊断及鉴别诊断。方法：回顾性分析了10例颈静脉孔区神经鞘瘤的CT和MRI影像资料。CT检查6例,其中4例作增强扫描,MR检查10例,其中8例作增强扫描,结果：根据CT和MRI表现颈静脉孔神经鞘瘤分为A,B,C三型,A型4例,B型1例,C型5例。神经鞘瘤易发生囊变,注射造影剂后肿瘤不均匀强化。结论：CT与MRI相结合,能更全面地为临床提供诊断,鉴别诊断及治疗所需要的信息,为治疗方法的选择提供可靠的依据。     

Hindered diffusion of MRI contrast agents in rat brain extracellular micro‐environment assessed by acquisition of dynamic T1 and T2 maps

The knowledge of brain tissues characteristics (such as extracellular space and tortuosity) represents valuable information for the design of optimal MR probes for specific biomarkers targeting. This work proposes a methodology based on dynamic acquisition of relaxation time maps to quantify in vivo MRI contrast agent concentration after intra‐cerebral injection in rat brain. It was applied to estimate the hindered diffusion in brain tissues of five contrast agents with different hydrodynamic diameters (Dotarem® ≈ 1 nm, P846 ≈ 4 nm, P792 ≈ 7 nm, P904 ≈ 22 nm and Gd‐based emulsion ≈ 170 nm). In vivo apparent diffusion coefficients were compared with those estimated in an obstacle‐free medium to determine brain extracellular space and tortuosity. At a 2 h imaging timescale, all contrast agents except the Gd‐based emulsion exhibited significant diffusion through brain tissues, with characteristic times compatible with MR molecular imaging (<70 min to diffuse between two capillaries). In conclusion, our experiments indicate that MRI contrast agents with sizes up to 22 nm can be used to perform molecular imaging on intra‐cerebral biomarkers. Our quantification methodology allows a precise estimation of apparent diffusion coefficients, which is helpful to calibrate optimal timing between contrast agent injection and MRI observation for molecular imaging studies. Copyright © 2012 John Wiley & Sons, Ltd.     

A novel Tc‐99 m and fluorescence labeled peptide as a multimodal imaging agent for targeting angiogenesis in a murine tumor model

The serine–aspartic acid–valine (SDV) peptide binds specifically to integrin α_Vβ₃. In the present study, we successfully developed a TAMRA–GHEG–ECG–SDV peptide labeled with both Tc‐99 m and TAMRA to target the integrin α_Vβ₃ of tumor cells; furthermore, we evaluated the diagnostic performance of Tc‐99 m TAMRA–GHEG–ECG–SDV as a dual‐modality imaging agent for tumor of the murine model. TAMRA–GHEG–ECG–SDV was synthesized using Fmoc solid‐phase peptide synthesis. Radiolabeling of TAMRA–GHEG–ECG–SDV with Tc‐99 m was done using ligand exchange methods. Labeling stability and cytotoxicity studies were performed. Gamma camera imaging, biodistribution and ex vivo imaging studies were performed in murine models with HT‐1080 and HT‐29 tumors. A tumor tissue slide was prepared and analyzed using confocal microscopy. After radiolabeling procedures with Tc‐99 m, the Tc‐99 m TAMRA–GHEG–ECG–SDV complexes were prepared in high yield (>99%). In the gamma camera imaging study, a substantial uptake of Tc‐99 m TAMRA–GHEG–ECG–SDV into HT‐1080 tumor (integrin α_Vβ₃ positive) and low uptake of Tc‐99 m TAMRA–GHEG–ECG–SDV into HT‐29 tumor (integrin α_Vβ₃ negative) were demonstrated. A competition study revealed that HT‐1080 tumor uptake was effectively blocked by the co‐injection of an excess concentration of SDV. Specific uptake of Tc‐99 m TAMRA–GHEG–ECG–SDV was confirmed by biodistribution, ex vivo imaging and confocal microscopy studies. Our in vivo and in vitro studies revealed substantial uptake of Tc‐99 m TAMRA–GHEG–ECG–SDV in the integrin α_Vβ₃‐positive tumor. Tc‐99 m TAMRA–GHEG–ECG–SDV could be a good candidate for a dual‐modality imaging agent targeting tumor angiogenesis. Copyright © 2016 John Wiley & Sons, Ltd.     

Intra-articular tracking of adipose-derived stem cells by chitosan-conjugated iron oxide nanoparticles in a rat osteoarthritis model

Adipose-derived stem cells (ADSCs) hold great potential in cartilage tissue engineering due to their multipotency and ease of availability. MRI is an effective and noninvasive imaging approach to track cells and observe new tissue regeneration. It is essential to find a compatible and efficient imaging reagent without affecting the stemness of ADSCs. Herein, we developed chitosan-modified iron oxide nanoparticles (IO-CS) as the T₂ contrast reagent with good cell compatibility and high cellular uptake efficiency and used IO-CS for ADSC intra-articular imaging in a rat osteoarthritis (OA) model. TEM demonstrated the great morphology and size distribution of IO-CS nanoparticles with the size of 17 nm. Magnetization (29.4 emu per g) and MRI tests confirmed (R₂ of 184 mM⁻¹ s⁻¹) the feasibility of IO-CS nanoparticles as an MRI contrast reagent. In addition, the IO-CS nanoparticles showed good cellular compatibility and high labeling efficiency as compared to the commercial agent ferumoxytol. Moreover, incorporation of IO-CS nanoparticles did not alter the adipogenic, osteogenic and chondrogenic differentiation ability of ADSCs. Furthermore, the MRI transverse R₂ maps showed a persistence time of the IO-CS nanoparticles in ADSCs of 6 days in vitro. Then, we investigated the imaging capability of the IO-CS nanoparticle-labeled ADSCs in vivo with MRI for 5 weeks. The histological studies demonstrated the intra-articular biodistribution of the IO-CS nanoparticles, including in the cartilage superficial layer, synovial sublining layer, periosteum and bone marrow cavity. They provided systemic distribution information of the ADSCs in the OA rat model. In summary, we developed an accessible and effective T₂ imaging reagent with good biocompatibility and maintenance of the stemness of ADSCs. This showed the potential translational application of IO-CS nanoparticles as an MRI reagent in cartilage tissue engineering.

The chitosan modified IO-CS nanoparticles are biocompatible and efficient MRI reagents for the adipose-derived stem cell labeling and tracking in an osteoarthritis rat model.     

Breast Cancer Cells Imaging By Targeting Methionine Transporters with Gadolinium-Based Nanoprobe

Purpose

Early cancer diagnosis using MRI imaging is of high global interest as a non-invasive and powerful modality. In this study, methionine was conjugated on gadolinium-based mesoporous silica nanospheres to evaluate intra-cellular uptake and its accumulation in human breast cancer cells.

Procedures

The contrast agent was synthesized and characterized using different techniques including N₂ physisorption, thermal gravimetric analysis, dynamic light scattering, and inductively coupled plasma atomic emission spectroscopy (ICP-AES). The intra-cellular uptake of Gd³⁺ was measured by ICP-AES, fluorescent microscopy, and flow cytometry. Finally, cellular and tumor MR imaging were performed to determine in vitro and in vivo relaxometry.

Results

According to the results, the contrast agents accumulated in tumor cells both in vitro and in vivo. There was no significant cellular toxicity on either normal or cancer cells along with strong intense signal on T ₁ compared to the unlabeled cells.

Conclusions

The results showed that the novel contrast agent could become a useful tool in early detection of cancer.     

胰岛细胞瘤的影像学表现（附10例分析）

目的胰岛细胞瘤较少见，目前对胰岛细胞瘤的CT表现报道较多，MRI表现报道较少。本研究分析胰岛细胞瘤的CT及MRI表现，着重探讨MRI的诊断价值。方法回顾性分析经手术病理证实的10例胰岛细胞瘤的CT及MRI表现。结果10例胰岛细胞瘤中，8例为功能性胰岛细胞瘤，2例为无功能性胰岛细胞瘤，其中4例为恶性。胰岛素瘤普通CT多表现为等密度，轻度强化，较易漏诊。MRI多表现为T1WI低信号，T2WI高信号，常规增强后轻度强化，动态MRI增强早期可明显强化。功能性胰岛细胞瘤体积多较小，无功能性或恶性胰岛细胞瘤体积多较大。恶性胰岛细胞瘤多伴肝脏或淋巴结转移。结论胰岛细胞瘤的影像学表现具有一定的特征性，MRI较常规CT能提供更多的诊断信息．尤其是动态增强MRI。     

Multimodal imaging enables early detection and characterization of changes in tumor permeability of brain metastases

Our goal was to develop strategies to quantify the accumulation of model therapeutics in small brain metastases using multimodal imaging, in order to enhance the potential for successful treatment. Human melanoma cells were injected into the left cardiac ventricle of immunodeficient mice. Bioluminescent, MR and PET imaging were applied to evaluate the limits of detection and potential for contrast agent extravasation in small brain metastases. A pharmacokinetic model was applied to estimate vascular permeability. Bioluminescent imaging after injecting d-luciferin (molecular weight (MW) 320 D) suggested that tumor cell extravasation had already occurred at week 1, which was confirmed by histology. 7 T T1w MRI at week 4 was able to detect non-leaky 100 μm sized lesions and leaky tumors with diameters down to 200 μm after contrast injection at week 5. PET imaging showed that ¹⁸F-FLT (MW 244 Da) accumulated in the brain at week 4. Gadolinium-based MRI tracers (MW 559 Da and 2.066 kDa) extravasated after 5 weeks (tumor diameter 600 μm), and the lower MW agent cleared more rapidly from the tumor (mean apparent permeabilities 2.27 × 10^− 5 cm/s versus 1.12 × 10^− 5 cm/s). PET imaging further demonstrated tumor permeability to ⁶⁴Cu-BSA (MW 65.55 kDa) at week 6 (tumor diameter 700 μm). In conclusion, high field T1w MRI without contrast may improve the detection limit of small brain metastases, allowing for earlier diagnosis of patients, although the smallest lesions detected with T1w MRI were permeable only to d-luciferin and the amphipathic small molecule ¹⁸F-FLT. Different-sized MR and PET contrast agents demonstrated the gradual increase in leakiness of the blood tumor barrier during metastatic progression, which could guide clinicians in choosing tailored treatment strategies.     

MRI Monitoring and Quantification of Ultrasound-Mediated Delivery of Liposomes Dually Labeled with Gadolinium and Fluorophore through the Blood-Brain Barrier

Magnetic resonance image-guided focused ultrasound has emerged as a viable non-invasive technique for the treatment of central nervous system-related diseases/disorders. Application of mechanical and thermal effects associated with focused transcranial ultrasound has been studied extensively in pre-clinical models, which has paved the way for clinical trials. However, in vivo treatment evaluation techniques on drug delivery application via blood–brain barrier opening has not been fully explored. Current treatment evaluation techniques via magnetic resonance imaging are hindered by systemic toxicity resulting from free gadolinium delivery. Here we propose a novel treatment evaluation strategy to overcome limitations by (i) synthesizing liposomes that are dually labeled with gadolinium, a magnetic resonance imaging (MRI) contrast agent, and rhodamine, a fluorophore; (ii) applying a focused ultrasound (FUS)-mediated BBB opening technique to deliver the liposomes across vascular barriers, achieving local gadolinium enhancement while reducing systemic and unwanted regional toxic effects associated with free gadolinium; and (iii) utilizing the MRI modality to confirm the delivery as it is already included in the FUS treatment in clinic. Liposomes were secondarily labeled with a fluorescent marker to confirm results obtained by MRI quantification postmortem. Two different sizes, 77.5 nm (group A) and 140 nm (group B), of gadolinium- and fluorescence-labeled liposomes were fabricated using thin-film hydration followed by extrusion methods and determined their stability up to 6 h under physiologic conditions. Gadolinium signal was detected on contrast-enhanced T1-weighted MRI 5 h after the delivery of liposomes via the BBB opening approach with an ultrasound pulse of 0.42 MPa (estimate in water) combined with microbubbles. MRI contrast was enhanced significantly in sonicated regions compared with non-sonicated regions of the brain. This was due to the accumulation of labeled liposomes, which was confirmed by detection of rhodamine fluorescence in histologic sections. The relative increase in MRI signal intensity was greater for smaller liposomes (mean diameter = 77.5 nm) than larger liposomes (mean diameter = 140 nm), which suggested a greater accumulation of the smaller liposomes in the brain after ultrasound-mediated opening of the BBB. Our findings suggest that the dual-labeled nanocarrier platform can be established, the FUS-mediated BBB opening approach can be used to deliver it through vascular barriers and MRI can be used to evaluate the extent of nanocarrier delivery.     

Interventions to Reduce Anxiety,Distress, and the Need for Sedation in Pediatric Patients Undergoing Magnetic Resonance Imaging: A Systematic Review

BackgroundChildren undergoing magnetic resonance imaging (MRI) scans can experience anxiety, claustrophobia, and fear during the scanning experience and often require sedation.ObjectiveThe aim of this systematic review was to determine what strategies are effective in reducing fear, anxiety, and claustrophobia and reduce the need for sedation in children undergoing MRI.MethodsA quantitative systematic review, according to the methodology of the Joanna Briggs Institute, was carried out. A systematic search of a number of databases was performed. Studies were then screened and critically appraised by two independent reviewers before being included in the review.ResultsIn total, eight studies met the inclusion criteria for the review, which assessed the following interventions: mock MRI, audiovisual (AV) systems, open MRI, photo diary, and cognitive strategies. Open MRI, mock MRI, AV systems, cognitive behavioral therapies, guided imagery, and pediatric preparation booklets were all found to have some positive effect on at least one outcome.ConclusionHealth care professionals working with children undergoing MRI may consider some of the strategies included in this review to implement in their practice to reduce anxiety and increase patient comfort, while reducing the need for sedation.     

Quantitative PET Imaging of VEGF Receptor Expression

Purpose  Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling pathway plays pivotal roles in regulating tumor angiogenesis. Quantitative positron emission tomography (PET) imaging of VEGFR will facilitate the planning of whether, and when, to start anti-angiogenic treatment and enable more robust and effective monitoring of such treatment. Materials and methods  VEGF₁₂₁ was conjugated with DOTA (1,4,7,10-tetra-azacylododecane N,N′,N′′,N′′′-tetraacetic acid) and then labeled with ⁶⁴Cu for PET imaging of mice bearing different-sized human glioblastoma U87MG tumors (n = 15). Western blotting and immunofluorescence staining of tumor tissue was carried out to correlate with/validate the imaging results. Results  The specific activity of ⁶⁴Cu-DOTA-VEGF₁₂₁ was 3.2 GBq/mg. The uptake of ⁶⁴Cu-DOTA-VEGF₁₂₁ in the tumor peaked when the tumor size was about 100–250 mm³. Both small and large tumors had lower tracer uptake indicating a narrow range of tumor size with high VEGFR-2 expression. All tumors had similarly low VEGFR-1 expression. Most importantly, the tumor uptake value obtained from PET imaging had good linear correlation with the relative tumor tissue VEGFR-2 expression as measured by Western blot, where r ² equals 0.68 based on the PET uptake at 4 h post-injection. Histology of the frozen tumor tissue corroborates well with the imaging results. Conclusion  The tumor uptake of ⁶⁴Cu-DOTA-VEGF₁₂₁ measured by small-animal PET imaging reflects tumor VEGFR-2 expression level in vivo. Such correlation may facilitate future treatment planning and treatment monitoring of cancer and potentially other angiogenesis-related diseases. Kai Chen and Weibo Cai contributed equally to this work.