Search

Objective: To develop and characterize a clinically applicable, fast and efficient method for stem cell labeling with ferucarbotran and protamine for depiction with clinical MRI.Methods: The hydrodynamic diameter, zeta potential and relaxivities of ferucarbotran and varying concentrations of protamine were measured. Once the optimized ratio was found, human mesenchymal stem cells (MSCs) were labeled at varying incubation times (1-24 h). Viability was assessed via Trypan blue exclusion testing. 150,000 labeled cells in Ficoll solution were imaged with T1-, T2- and T2*-weighted sequences at 3 T, and relaxation rates were calculated.Results: Varying the concentrations of protamine allows for easy modification of the physicochemical properties. Simple incubation with ferucarbotran alone resulted in efficient labeling after 24 h of incubation while assisted labeling with protamine resulted in similar results after only 1 h. Cell viability remained unaffected. R2 and R2* relaxation rates were drastically increased. Electron microscopy confirmed intracellular iron oxide uptake in lysosomes. Relaxation times correlated with results from ICP-AES.Conclusion: Our results show internalization of ferucarbotran can be accelerated in MSCs with protamine, an approved heparin antagonist and potentially clinically applicable uptake-enhancing agent. [ABSTRACT FROM AUTHOR]

Magnetic resonance (MR) imaging of bone marrow provides a noninvasive diagnosis of the vascularity, cell quantity, and composition of the normal and pathological bone marrow. This article reviews new and evolving techniques for bone marrow MR imaging with a special focus on translational and clinical applications. Evaluations of bone marrow perfusion with standard small molecular contrast agents and, more recently, with macromolecular contrast agents are currently being applied for therapy monitoring. Cell-specific contrast agents are expected to improve the sensitivity and specificity of bone marrow MR imaging. Novel cellular and molecular imaging techniques for the depiction of cell metabolism and specific biochemical pathways are discussed. Cell tracking techniques may allow specific diagnoses of inflammatory processes as well as monitoring of novel therapies based on stem cells. Future developments of fusion imaging techniques and bifunctional contrast agents are directed to combine comprehensive information about bone marrow structure and function with targeted and image-guided therapies. [ABSTRACT FROM AUTHOR]

Adaptability, sensitivity, resolution and non-invasiveness are the attributes that have contributed to the longstanding use of light as an investigational tool and form the basis of optical imaging (OI). OI, which encompasses numerous techniques and methods, is rapid (<5 min), inexpensive, noninvasive, nontoxic (no radiation) and has molecular (single-cell) sensitivity, which is equal to that of conventional nuclear imaging and several orders of magnitude greater than MRI. This article provides a comprehensive overview of emerging applications of OI-based techniques for in vivo monitoring of new stem cell-based therapies. Different fluorochromes for cell labeling, labeling methods and OI-based cell-tracking techniques will be reviewed with respect to their technical principles, current applications and aims for clinical translation. Advantages and limitations of these new OI-based cell-tracking techniques will be discussed. Non-invasive mapping of cells labeled with fluorochromes or OI marker genes has the potential to evolve further within the clinical realm. [ABSTRACT FROM AUTHOR]

Abstract Purpose Peri-tumoral inflammation is a common tumor response that plays a central role in tumor invasion and metastasis, and inflammatory cell recruitment is essential to this process. The purpose of this study was to determine whether injected fluorescently-labeled monocytes accumulate within murine breast tumors and are visible with optical imaging. Materials and methods Murine monocytes were labeled with the fluorescent dye DiD and subsequently injected intravenously into 6 transgenic MMTV-PymT tumor-bearing mice and 6 FVB/n control mice without tumors. Optical imaging (OI) was performed before and after cell injection. Ratios of post-injection to pre-injection fluorescent signal intensity of the tumors (MMTV-PymT mice) and mammary tissue (FVB/n controls) were calculated and statistically compared. Results MMTV-PymT breast tumors had an average post/pre signal intensity ratio of 1.8+/- 0.2 (range 1.1-2.7). Control mammary tissue had an average post/pre signal intensity ratio of 1.1 +/- 0.1 (range, 0.4 to 1.4). The p-value for the difference between the ratios was less than 0.05. Confocal fluorescence microscopy confirmed the presence of DiD-labeled cells within the breast tumors. Conclusion Murine monocytes accumulate at the site of breast cancer development in this transgenic model, providing evidence that peri-tumoral inflammatory cell recruitment can be evaluated non-invasively using optical imaging.

Abstract Background The development of postoperative granulation tissue is one of the main postoperative risks after lumbar spine surgery. This granulation tissue may lead to persistent or new clinical symptoms or complicate a follow up surgery. A sensitive non-invasive imaging technique, that could diagnose this granulation tissue at the bedside, would help to develop appropriate treatments. Thus, the purpose of this study was to establish a fast and economic imaging tool for the diagnosis of granulation tissue after lumbar spine surgery, using a new integrated Optical Imaging (OI)/X-ray imaging system and the FDA-approved fluorescent contrast agent Indocyanine Green (ICG). Methods 12 male Sprague Dawley rats underwent intervertebral disk surgery. Imaging of the operated lumbar spine was done with the integrated OI/X-ray system at 7 and 14 days after surgery. 6 rats served as non-operated controls. OI/X-ray scans of all rats were acquired before and after intravenous injection of the FDA-approved fluorescent dye Indocyanine Green (ICG) at a dose of 1 mg/kg or 10 mg/kg. The fluorescence signal of the paravertebral soft tissues was compared between different groups of rats using Wilcoxon-tests. Lumbar spines and paravertebral soft tissues were further processed with histopathology. Results In both dose groups, ICG provided a significant enhancement of soft tissue in the area of surgery, which corresponded with granulation tissue on histopathology. The peak and time interval of fluorescence enhancement was significantly higher using 10 mg/kg dose of ICG compared to the 1 mg/kg ICG dose. The levels of significance were p < 0.05. Fusion of OI data with X-rays allowed an accurate anatomical localization of the enhancing granulation tissue. Conclusion ICG-enhanced OI is a suitable technique to diagnose granulation tissue after lumbar spine surgery. This new imaging technique may be clinically applicable for postoperative treatment monitoring. It could be also used to evaluate the effect of anti-inflammatory drugs and may even allow evaluations at the bedside with new hand-held OI scanners.

Senescent cells play a vital role in the pathogenesis of musculoskeletal (MSK) diseases, such as chronic inflammatory joint disorders, rheumatoid arthritis (RA), and osteoarthritis (OA). Cellular senescence in articular joints represents a response of local cells to persistent stress that leads to cell-cycle arrest and enhanced production of inflammatory cytokines, which in turn perpetuates joint damage and leads to significant morbidities in afflicted patients. It has been recently discovered that clearance of senescent cells by novel "senolytic" therapies can attenuate the chronic inflammatory microenvironment of RA and OA, preventing further disease progression and supporting healing processes. To identify patients who might benefit from these new senolytic therapies and monitor therapy response, there is an unmet need to identify and map senescent cells in articular joints and related musculoskeletal tissues. To fill this gap, new imaging biomarkers are being developed to detect and characterize senescent cells in human joints and musculoskeletal tissues. This review article will provide an overview of these efforts. New imaging biomarkers for senescence cells are expected to significantly improve the specificity of state-of-the-art imaging technologies for diagnosing musculoskeletal disorders., (© 2024. The Author(s), under exclusive licence to International Skeletal Society (ISS).)

Artificial intelligence (AI) is transforming the medical imaging of adult patients. However, its utilization in pediatric oncology imaging remains constrained, in part due to the inherent scarcity of data associated with childhood cancers. Pediatric cancers are rare, and imaging technologies are evolving rapidly, leading to insufficient data of a particular type to effectively train these algorithms. The small market size of pediatric patients compared with adult patients could also contribute to this challenge, as market size is a driver of commercialization. This review provides an overview of the current state of AI applications for pediatric cancer imaging, including applications for medical image acquisition, processing, reconstruction, segmentation, diagnosis, staging, and treatment response monitoring. Although current developments are promising, impediments due to the diverse anatomies of growing children and nonstandardized imaging protocols have led to limited clinical translation thus far. Opportunities include leveraging reconstruction algorithms to achieve accelerated low-dose imaging and automating the generation of metric-based staging and treatment monitoring scores. Transfer learning of adult-based AI models to pediatric cancers, multiinstitutional data sharing, and ethical data privacy practices for pediatric patients with rare cancers will be keys to unlocking the full potential of AI for clinical translation and improving outcomes for these young patients.

Background: New immunotherapies activate tumor-associated macrophages (TAMs) in the osteosarcoma microenvironment. Iron oxide nanoparticles (IONPs) are phagocytosed by TAMs and, therefore, enable TAM detection on T2*- and T2-weighted magnetic resonance images. We assessed the repeatability and reproducibility of T2*- and T2-mapping of osteosarcomas in a mouse model., Methods: Fifteen BALB/c mice bearing-murine osteosarcomas underwent magnetic resonance imaging (MRI) on 3-T and 7-T scanners before and after intravenous IONP infusion, using T2*-weighted multi-gradient-echo, T2-weighted fast spin-echo, and T2-weighted multi-echo sequences. Each sequence was repeated twice. Tumor T2 and T2* relaxation times were measured twice by two independent investigators. Repeatability and reproducibility of measurements were assessed., Results: We found excellent agreement between duplicate acquisitions for both T2* and T2 measurements at either magnetic field strength, by the same individual (repeatability), and between individuals (reproducibility). The repeatability concordance correlation coefficient (CCC) for T2* values were 0.99 (coefficients of variation (CoV) 4.43%) for reader 1 and 0.98 (CoV 5.82%) for reader 2. The reproducibility of T2* values between the two readers was 0.99 (CoV 3.32%) for the first acquisitions and 0.99 (CoV 6.30%) for the second acquisitions. Regarding T2 values, the repeatability of CCC was similar for both readers, 0.98 (CoV 3.64% for reader 1 and 4.45% for reader 2). The CCC of the reproducibility of T2 was 0.99 (CoV 3.1%) for the first acquisition and 0.98 (CoV 4.38%) for the second acquisition., Conclusions: Our results demonstrated high repeatability and reproducibility of quantitative T2* and T2 mapping for monitoring the presence of TAMs in osteosarcomas., Relevance Statement: T2* and T2 measurements of osteosarcomas on IONP-enhanced MRI could allow identifying patients who may benefit from TAM-modulating immunotherapies and for monitoring treatment response. The technique described here could be also applied across a wide range of other solid tumors., Key Points: • Optimal integration of TAM-modulating immunotherapies with conventional chemotherapy remains poorly elucidated. • We found high repeatability of T2* and T2 measurements of osteosarcomas in a mouse model, both with and without IONPs contrast, at 3-T and 7-T MRI field strengths. • T2 and T2* mapping may be used to determine response to macrophage-modulating cancer immunotherapies., (© 2024. The Author(s).)

Once considered a tissue culture-specific phenomenon, cellular senescence has now been linked to various biological processes with both beneficial and detrimental roles in humans, rodents and other species. Much of our understanding of senescent cell biology still originates from tissue culture studies, where each cell in the culture is driven to an irreversible cell cycle arrest. By contrast, in tissues, these cells are relatively rare and difficult to characterize, and it is now established that fully differentiated, postmitotic cells can also acquire a senescence phenotype. The SenNet Biomarkers Working Group was formed to provide recommendations for the use of cellular senescence markers to identify and characterize senescent cells in tissues. Here, we provide recommendations for detecting senescent cells in different tissues based on a comprehensive analysis of existing literature reporting senescence markers in 14 tissues in mice and humans. We discuss some of the recent advances in detecting and characterizing cellular senescence, including molecular senescence signatures and morphological features, and the use of circulating markers. We aim for this work to be a valuable resource for both seasoned investigators in senescence-related studies and newcomers to the field., (© 2024. Springer Nature Limited.)

Objectives: A novel clinically translatable iron oxide nanoparticle (IOP) is currently being tested in phase 2 clinical trials as a magnetic resonance imaging (MRI) contrast agent for hepatocellular carcinoma diagnosis. The purpose of our study is to evaluate if this IOP can detect activation of tumor-associated macrophages (TAMs) due to CD47 mAb-targeted immunotherapy in 2 mouse models of osteosarcoma., Materials and Methods: The toxicity, biodistribution, and pharmacokinetics of IOP were evaluated in 77 female and 77 male rats. Then, 24 female BALB/c mice with intratibial murine K7M2 tumors and 24 female NOD scid gamma mice with intratibial human 143B osteosarcoma xenografts were treated with either CD47 mAb (n = 12) or control antibody (n = 12). In each treatment group, 6 mice underwent MRI scans before and after intravenous infusion of either IOP or ferumoxytol (30 mg Fe/kg). Tumor T2* values and TAM markers F4/80, CD80, CD206, and Prussian blue staining were compared between different experimental groups using exact 2-sided Wilcoxon rank sum tests., Results: Biodistribution and safety evaluations of IOP were favorable for doses of less than 50 mg Fe/kg body weight in female and male rats. Both IOP and ferumoxytol caused negative enhancement (darkening) of the tumor tissue. Both murine and human osteosarcoma tumors treated with CD47 mAb demonstrated significantly shortened T2* relaxation times after infusion of IOP or ferumoxytol compared with controls (all P 's < 0.05). Higher levels of F4/80 + CD80 + were found in murine and human osteosarcomas treated with CD47 mAb compared with sham-treated controls (all P 's < 0.05). In addition, murine CD47 mAb-treated tumors after infusion of either IOP or ferumoxytol showed significantly higher numbers of Prussian blue-positive cells compared with controls ( P < 0.05). There was no significant difference of F4/80 + CD206 + cells among any of the groups (all P 's > 0.05)., Conclusions: Iron oxide nanoparticle-enhanced MRI can be used to diagnose CD47 mAb-mediated TAM-activation in osteosarcomas., Competing Interests: Conflicts of interest: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The delivery of intravenously administered cancer therapeutics to brain tumors is limited by the blood-brain barrier. A method to directly image the accumulation and distribution of macromolecules in brain tumors in vivo would greatly enhance our ability to understand and optimize drug delivery in preclinical models. This protocol describes a method for real-time in vivo tracking of intravenously administered fluorescent-labeled nanoparticles with two-photon intravital microscopy (2P-IVM) in a mouse model of glioblastoma (GBM). The protocol contains a multi-step description of the procedure, including anesthesia and analgesia of experimental animals, creating a cranial window, GBM cell implantation, placing a head bar, conducting 2P-IVM studies, and post-surgical care for long-term follow-up studies. We show representative 2P-IVM imaging sessions and image analysis, examine the advantages and disadvantages of this technology, and discuss potential applications. This method can be easily modified and adapted for different research questions in the field of in vivo preclinical brain imaging.

Lymphoma is one of the most common types of cancer for children (ages 0 to 19). Due to the reduced radiation exposure, PET/MR systems that allow simultaneous PET and MR imaging have become the standard of care for diagnosing cancers and monitoring tumor response to therapy in the pediatric population. In this work, we developed a multimodal deep learning algorithm for automatic pediatric lymphoma detection using PET and MRI. Through innovative designs such as standardized uptake value (SUV) guided tumor candidate generation, location aware classification model learning and weighted multimodal feature fusion, our algorithm can be effectively trained with limited data and achieved superior tumor detection performance over the state-of-the-art in our experiments., (©2023 AMIA - All rights reserved.)

We hypothesized that 18 F-FDG PET/MRI would reveal thymus activation in children after coronavirus disease 2019 (COVID-19) vaccination. Methods: We retrospectively analyzed the 18 F-FDG PET/MRI scans of 6 children with extrathoracic cancer before and after COVID-19 vaccination. We compared pre- and postvaccination SUV max , mean apparent diffusion coefficient, and size of the thymus and axillary lymph nodes using a paired t test. Results: All 6 patients showed increased 18 F-FDG uptake in the axillary lymph nodes after vaccination ( P = 0.03). In addition, these patients demonstrated increased 18 F-FDG uptake in the thymus. When compared with baseline, the postvaccination scans of these patients demonstrated an increased mean thymic SUV ( P = 0.02), increased thymic size ( P = 0.13), and decreased thymic mean apparent diffusion coefficient ( P = 0.08). Conclusion: 18 F-FDG PET/MRI can reveal thymus activation in addition to local lymph node reactions in children after COVID-19 vaccination., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective: To compare tumor therapy response assessments with whole-body diffusion-weighted imaging (WB-DWI) and 18F-fluorodeoxyglucose ([ 18 F]FDG) PET/MRI in pediatric patients with Hodgkin lymphoma and non-Hodgkin lymphoma., Materials and Methods: In a retrospective, non-randomized single-center study, we reviewed serial simultaneous WB-DWI and [ 18 F]FDG PET/MRI scans of 45 children and young adults (27 males; mean age, 13 years ± 5 [standard deviation]; age range, 1-21 years) with Hodgkin lymphoma (n = 20) and non-Hodgkin lymphoma (n = 25) between February 2018 and October 2022. We measured minimum tumor apparent diffusion coefficient (ADCmin) and maximum standardized uptake value (SUVmax) of up to six target lesions and assessed therapy response according to Lugano criteria and modified criteria for WB-DWI. We evaluated the agreement between WB-DWI- and [ 18 F]FDG PET/MRI-based response classifications with Gwet's agreement coefficient (AC)., Results: After induction chemotherapy, 95% (19 of 20) of patients with Hodgkin lymphoma and 72% (18 of 25) of patients with non-Hodgkin lymphoma showed concordant response in tumor metabolism and proton diffusion. We found a high agreement between treatment response assessments on WB-DWI and [ 18 F]FDG PET/MRI (Gwet's AC = 0.94; 95% confidence interval [CI]: 0.82, 1.00) in patients with Hodgkin lymphoma, and a lower agreement for patients with non-Hodgkin lymphoma (Gwet's AC = 0.66; 95% CI: 0.43, 0.90). After completion of therapy, there was an excellent agreement between WB-DWI and [ 18 F]FDG PET/MRI response assessments (Gwet's AC = 0.97; 95% CI: 0.91, 1)., Conclusion: Therapy response of Hodgkin lymphoma can be evaluated with either [ 18 F]FDG PET or WB-DWI, whereas patients with non-Hodgkin lymphoma may benefit from a combined approach., Clinical Relevance Statement: Hodgkin lymphoma and non-Hodgkin lymphoma exhibit different patterns of tumor response to induction chemotherapy on diffusion-weighted MRI and PET/MRI., Key Points: • Diffusion-weighted imaging has been proposed as an alternative imaging to assess tumor response without ionizing radiation. • After induction therapy, whole-body diffusion-weighted imaging and PET/MRI revealed a higher agreement in patients with Hodgkin lymphoma than in those with non-Hodgkin lymphoma. • At the end of therapy, whole-body diffusion-weighted imaging and PET/MRI revealed an excellent agreement for overall tumor therapy responses for all lymphoma types., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Purposes: This study aims to ascertain the prevalence of cavitations in pulmonary metastases among pediatric and young adult patients with sarcoma undergoing tyrosine kinase inhibitor (TKI) therapy, and assess whether cavitation can predict clinical response and survival outcomes., Methods: In a single-center retrospective analysis, we examined chest computed tomography (CT) scans of 17 patients (median age 16 years; age range: 4-25 years) with histopathologically confirmed bone (n = 10) or soft tissue (n = 7) sarcoma who underwent TKI treatment for lung metastases. The interval between TKI initiation and the onset of lung nodule cavitation and tumor regrowth were assessed. The combination of all imaging studies and clinical data served as the reference standard for clinical responses. Progression-free survival (PFS) was compared between patients with cavitating and solid nodules using Kaplan-Meier survival analysis and log-rank test., Results: Five out of 17 patients (29%) exhibited cavitation of pulmonary nodules during TKI therapy. The median time from TKI initiation to the first observed cavitation was 79 days (range: 46-261 days). At the time of cavitation, all patients demonstrated stable disease. When the cavities began to fill with solid tumor, 60% (3/5) of patients exhibited progression in other pulmonary nodules. The median PFS for patients with cavitated pulmonary nodules after TKI treatment (6.7 months) was significantly longer compared to patients without cavitated nodules (3.8 months; log-rank p-value = .03)., Conclusions: Cavitation of metastatic pulmonary nodules in sarcoma patients undergoing TKI treatment is indicative of non-progressive disease, and significantly correlates with PFS., (© 2023 Wiley Periodicals LLC.)

Objectives: Iron oxide nanoparticles have been used to track the accumulation of chimeric antigen receptor (CAR) T cells with magnetic resonance imaging (MRI). However, the only nanoparticle available for clinical applications to date, ferumoxytol, has caused rare but severe anaphylactic reactions. MegaPro nanoparticles (MegaPro-NPs) provide an improved safety profile. We evaluated whether MegaPro-NPs can be applied for in vivo tracking of CAR T cells in a mouse model of glioblastoma multiforme., Materials and Methods: We labeled tumor-targeted CD70CAR (8R-70CAR) T cells and non-tumor-targeted controls with MegaPro-NPs, followed by inductively coupled plasma optical emission spectroscopy, Prussian blue staining, and cell viability assays. Next, we treated 42 NRG mice bearing U87-MG/eGFP-fLuc glioblastoma multiforme xenografts with MegaPro-NP-labeled/unlabeled CAR T cells or labeled untargeted T cells and performed serial MRI, magnetic particle imaging, and histology studies. The Kruskal-Wallis test was conducted to evaluate overall group differences, and the Mann-Whitney U test was applied to compare the pairs of groups., Results: MegaPro-NP-labeled CAR T cells demonstrated significantly increased iron uptake compared with unlabeled controls ( P < 0.01). Cell viability, activation, and exhaustion markers were not significantly different between the 2 groups ( P > 0.05). In vivo, tumor T2* relaxation times were significantly lower after treatment with MegaPro-NP-labeled CAR T cells compared with untargeted T cells ( P < 0.01). There is no significant difference in tumor growth inhibition between mice injected with labeled and unlabeled CAR T cells., Conclusions: MegaPro-NPs can be used for in vivo tracking of CAR T cells. Because MegaPro-NPs recently completed phase II clinical trial investigation as an MRI contrast agent, MegaPro-NP is expected to be applied to track CAR T cells in cancer immunotherapy trials in the near future., Competing Interests: Conflicts of interest and sources of funding: This work was supported by the ReMission Alliance Against Brain Tumors and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NIH/NICHD, grant number R01HD103638). Infrastructure support was provided by an NIH S10 Shared Instrumentation Grant (S10RR026917-01, PI Michael Moseley, PhD), the Stanford Center for Innovation in In Vivo Imaging (SCi 3 ), the Canary Preclinical Core Imaging Facility (Canary Center at Stanford, Stanford University), and an NCI Cancer Center Support Grant (P30 CA124435-02). Dr Jianping Huang was supported by the Department of Defense (grant W81XWH-20-1-0726) for developing tumor-targeted CAR T cells. For the remaining authors, none were declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To compare the diagnostic accuracy of diffusion-weighted (DW)-MRI with b-values of 50 s/mm 2 and 800 s/mm 2 for the detection of bone marrow metastases in children and young adults with solid malignancies., Methods: In an institutional review board-approved prospective study, we performed 51 whole-body DW-MRI scans in 19 children and young adults (14 males, 5 females; age range: 1-25 years) with metastasized cancers before (n = 19 scans) and after (n = 32 scans) chemotherapy. Two readers determined the presence of focal bone marrow lesions in 10 anatomical areas. A third reader measured ADC and SNR of focal lesions and normal marrow. Simultaneously acquired 18 F-FDG-PET scans served as the standard of reference. Data of b = 50 s/mm 2 and 800 s/mm 2 images were compared with the Wilcoxon signed-rank test. Inter-reader agreement was evaluated with weighted kappa statistics., Results: The SNR of bone marrow metastases was significantly higher compared to normal bone marrow on b = 50 s/mm 2 (mean ± SD: 978.436 ± 1239.436 vs. 108.881 ± 109.813, p < 0.001) and b = 800 s/mm 2 DW-MRI (499.638 ± 612.721 vs. 86.280 ± 89.120; p < 0.001). On 30 out of 32 post-treatment DW-MRI scans, reconverted marrow demonstrated low signal with low ADC values (0.385 × 10 -3  ± 0.168 × 10 -3 mm 2 /s). The same number of metastases (556/588; 94.6%; p > 0.99) was detected on b = 50 s/mm 2 and 800 s/mm 2 images. However, both normal marrow and metastases exhibited low signals on ADC maps, limiting the ability to delineate metastases. The inter-reader agreement was substantial, with a weighted kappa of 0.783 and 0.778, respectively., Conclusion: Bone marrow metastases in children and young adults can be equally well detected on b = 50 s/mm 2 and 800 s/mm 2 images, but ADC values can be misleading., (© 2022. The Author(s), under exclusive licence to International Skeletal Society (ISS).)

T2* relaxometry is one of the established methods to measure the effect of superparamagnetic iron oxide nanoparticles on tumor tissues with magnetic resonance imaging (MRI). Iron oxide nanoparticles shorten the T1, T2, and T2* relaxation times of tumors. While the T1 effect is variable based on the size and composition of the nanoparticles, the T2 and T2* effects are usually predominant, and T2* measurements are the most time-efficient in a clinical context. Here, we present our approach to measuring tumor T2* relaxation times, using multi-echo gradient echo sequences, external software, and a standardized protocol for creating a T2* map with scanner-independent software. This facilitates the comparison of imaging data from different clinical scanners, different vendors, and co-clinical research work (i.e., tumor T2* data obtained in mouse models and patients). Once the software is installed, the T2 Fit Map plugin needs to be installed from the plugin manager. This protocol provides step-by-step procedural details, from importing the multi-echo gradient echo sequences into the software, to creating color-coded T2* maps and measuring tumor T2* relaxation times. The protocol can be applied to solid tumors in any body part and has been validated based on preclinical imaging data and clinical data in patients. This could facilitate tumor T2* measurements for multi-center clinical trials and improve the standardization and reproducibility of tumor T2* measurements in co-clinical and multi-center data analyses.

Preclinical imaging is a critical component in translational research with significant complexities in workflow and site differences in deployment. Importantly, the National Cancer Institute's (NCI) precision medicine initiative emphasizes the use of translational co-clinical oncology models to address the biological and molecular bases of cancer prevention and treatment. The use of oncology models, such as patient-derived tumor xenografts (PDX) and genetically engineered mouse models (GEMMs), has ushered in an era of co-clinical trials by which preclinical studies can inform clinical trials and protocols, thus bridging the translational divide in cancer research. Similarly, preclinical imaging fills a translational gap as an enabling technology for translational imaging research. Unlike clinical imaging, where equipment manufacturers strive to meet standards in practice at clinical sites, standards are neither fully developed nor implemented in preclinical imaging. This fundamentally limits the collection and reporting of metadata to qualify preclinical imaging studies, thereby hindering open science and impacting the reproducibility of co-clinical imaging research. To begin to address these issues, the NCI co-clinical imaging research program (CIRP) conducted a survey to identify metadata requirements for reproducible quantitative co-clinical imaging. The enclosed consensus-based report summarizes co-clinical imaging metadata information (CIMI) to support quantitative co-clinical imaging research with broad implications for capturing co-clinical data, enabling interoperability and data sharing, as well as potentially leading to updates to the preclinical Digital Imaging and Communications in Medicine (DICOM) standard.

Purpose: To develop a deep learning approach that enables ultra-low-dose, 1% of the standard clinical dosage (3 MBq/kg), ultrafast whole-body PET reconstruction in cancer imaging., Materials and Methods: In this Health Insurance Portability and Accountability Act-compliant study, serial fluorine 18-labeled fluorodeoxyglucose PET/MRI scans of pediatric patients with lymphoma were retrospectively collected from two cross-continental medical centers between July 2015 and March 2020. Global similarity between baseline and follow-up scans was used to develop Masked-LMCTrans, a longitudinal multimodality coattentional convolutional neural network (CNN) transformer that provides interaction and joint reasoning between serial PET/MRI scans from the same patient. Image quality of the reconstructed ultra-low-dose PET was evaluated in comparison with a simulated standard 1% PET image. The performance of Masked-LMCTrans was compared with that of CNNs with pure convolution operations (classic U-Net family), and the effect of different CNN encoders on feature representation was assessed. Statistical differences in the structural similarity index measure (SSIM), peak signal-to-noise ratio (PSNR), and visual information fidelity (VIF) were assessed by two-sample testing with the Wilcoxon signed rank t test., Results: The study included 21 patients (mean age, 15 years ± 7 [SD]; 12 female) in the primary cohort and 10 patients (mean age, 13 years ± 4; six female) in the external test cohort. Masked-LMCTrans-reconstructed follow-up PET images demonstrated significantly less noise and more detailed structure compared with simulated 1% extremely ultra-low-dose PET images. SSIM, PSNR, and VIF were significantly higher for Masked-LMCTrans-reconstructed PET ( P < .001), with improvements of 15.8%, 23.4%, and 186%, respectively., Conclusion: Masked-LMCTrans achieved high image quality reconstruction of 1% low-dose whole-body PET images. Keywords: Pediatrics, PET, Convolutional Neural Network (CNN), Dose Reduction Supplemental material is available for this article. © RSNA, 2023., Competing Interests: Disclosures of conflicts of interest: Y.R.J.W. Grant from the National Cancer Institute of the U.S. National Institutes of Health, grant number R01CA269231, and the Andrew McDonough B + Foundation. L.Q. No relevant relationships. N.D.S. National Institutes of Health Director's Early Independence Award DP5 (DP5OD031846), National Cancer Institute F99/K00 Predoctoral to Postdoctoral Fellow Transition Award (K00CA234954). X.L. No relevant relationships. J.W. No relevant relationships. K.E.H. No relevant relationships. A.J.T. No relevant relationships. S.G. No relevant relationships. X.X. No relevant relationships. A.P. No relevant relationships. D.R. Grant support from NCI; associate editor of Radiology: Artificial Intelligence. H.E.D.L. Grant from the National Cancer Institute of the US National Institutes of Health, grant number R01CA269231; 5R01AR054458-11, NIH/NIAMS Title: Monitoring Stem Cell Engraftment in Arthritic Joints with MR Imaging Dates: 8/01/2017-7/31/2023, Role: PI 10% effort; R01CA269231 NIH/NCI Title: Advanced Imaging Tools to Assess Cancer Therapeutics in Pediatric Patients, Dates: 2/1/2022-01/31/2027, Role: PI 10% effort; R01HD103638 NIH/NICHD Title: Theranostics for Pediatric Brain Cancer Dates: 4/15/2021-4/15/2026, Role: PI 20% effort; UG3CA268112 NIH/NCI Title: Cellular Senescence Network: New Imaging Tools for Arthritis Imaging; Dates: 10/1/2021-11/31/2026, Role: PI 10% effort; R21AR075863 NIH/NIAMS Title: Instant Stem Cell Labeling with a New Microfluidic Device Dates: 7/1/2019-6/30/2023 (one year NCE), Role: PI 5% effort; R21HD101129 Title: Imaging Chemotherapy-Induced Brain Damage in Pediatric Cancer Survivors Dates: 8/1/2020-7/31/2023 (one year NCE), Role: PI 5% effort; U24CA264298 NIH/NCI Title: Co-clinical research for imaging tumor associated macrophages Dates: 7/1/2021-6/30/2026, Role: Co-PI 10% effort; 5P30CA124435-10 NIH/NCI Title: Stanford Cancer Institute Support Grant (PI: Steven Artandi) Dates: 6/01/2017-5/31/2027, Role: Co-I 10% effort (H. Daldrup-Link, Codirector, Cancer Imaging & Early Detection Program); Cancer Research Institute Technology Impact Award Title: Mechanoporation creates new Biomarkers for Cancer Immunotherapy Dates: 7/1/2021-6/30/2023, Role: PI 1% effort; Sarcoma Foundation of America Title: Imaging response to CD47 mAb immunotherapy in pediatric patients with osteosarcoma Dates: 6/1/2020-5/31/2023, Role: PI 1% effort; R24OD019813-01 NIH Office of the Director Title: Expanding the Utility of Severe Combined ImmunoDeficient (SCID) pig models Dates: 5/1/2015-4/30/2025 Role: External Advisory Board Member (PI Christopher Tuggle); The ReMission Alliance Against Brain Tumors Title: Imaging CAR-T cells in Glioblastoma Dates: 9/1/2020-8/30/2023, Role: PI of subaward 5% effort; MegaPro Inc. Title: Evaluation of MegaPro Nanoparticles for MRI monitoring of Cancer Immunotherapy Dates: 7/1/2021-6/30/2023 Role: PI 1% effort; R01CA263500 NIH/NCI (PI C. Mackall) Title: Developing Safe and Effective GD2-CAR T Cell Therapy for Diffuse Midline Gliomas Dates: 7/1/2021–6/30/2026, Role: Co-Investigator 2% effort; Stanford Center for Artificial Intelligence in Medicine and Imaging (AIMI) Title: Standardized Therapy Response Assessments of Pediatric Cancers Dates: 11/1/2021–10/31/2023 Role: PI 2% effort; Patent: US6009342 Patent Assignee: University of California; Daldrup-Link, H.: Immunotherapy for cancer treatment using iron oxide nanoparticles; Patent: US20130344003 Patent Assignee: Stanford University; Daldrup-Link, H.: In vivo iron labeling of stem cells and tracking these labeled stem cells after their transplantation; Patent: US9579349, issued 2/28/17 Patent Assignee: Stanford University; Nejadnik H., Lenkov O., Daldrup-Link, H.: Compositions and methods for mesenchymal and/or chondrogenic differentiation of stem cells Patent: US20140271616 A Patent Assignee: Stanford University; Falconer R., Loadman P., Gill J.; Rao, J.; Daldrup H.E.: Activatable theranostic nanoparticles; Patent: WO 2015014756. Patent Assignee: Bradford University, UK and Stanford University, USA; Li K., Nejadnik H., Daldrup-Link, H.: Dual-modality Imaging Probe for Combined Localization and Apoptosis Detection of Stem Cells; Patent: US20180036435 Patent Assignee: Stanford University; Daldrup-Link, H., Mohanty S.: AntiWarburg Nanoparticles; Patent: WO/2018/217943 Patent Assignee: Stanford University; Co-Chair, Steering Committee, The NIH Common Fund's Cellular Senescence Network (SenNet) Program; Awards Committee, World Molecular Imaging Society (WMIS); MR Imaging Committee, Society for Pediatric Radiology (SPR) Diversity & Inclusion Committee, Society for Pediatric Radiology (SPR); Oncology Imaging Committee, Society for Pediatric Radiology (SPR); ad hoc reviewer, Nanotechnology (Nano) Study Section. NIH CSR (Center for Scientific Review); Ad Hoc Reviewer, ZRG1 SBIB-Q 03 Study Section; Biomedical Imaging & Bioengineering, Center for Scientific Reviews; reviewer for research grant applications for Emerson Collective Cancer Research Fund; reviewer for research grant applications for the Swiss Cancer Research Foundation; reviewer for the Florida Department of Health's Biomedical Research Program; reviewer for the Belgian Foundation Against Cancer; receipt of equipment, materials, drugs or other services from MegaPro Biomedical; Managing Director of Monasteria Press; associate editor for Radiology: Imaging Cancer; associate chair for Diversity, Department of Radiology, Stanford School of Medicine, Co-Program Director, Mentoring to AdVance womEN in Science (MAVENS) program, Stanford School of Medicine, Advisory committee member, Justice Diversity, Equity and Inclusion (JEDI) at the Stanford Cancer Institute (SCI)., (© 2023 by the Radiological Society of North America, Inc.)

Purpose: To assess and compare the diagnostic accuracy of whole-body (WB) DW-MRI with 2-[ 18 F]FDG PET for staging and treatment monitoring of children with Langerhans cell histiocytosis (LCH)., Methods: Twenty-three children with LCH underwent 2-[ 18 F]FDG PET and WB DW-MRI at baseline. Two nuclear medicine physicians and two radiologists independently assessed presence/absence of tumors in 8 anatomical areas. Sixteen children also performed 2-[ 18 F]FDG PET and WB DW-MRI at follow-up. One radiologist and one nuclear medicine physician revised follow-up scans and collected changes in tumor apparent diffusion (ADC) and standardized uptake values (SUV) before and after therapy in all detectable lesions. 2-[ 18 F]FDG PET results were considered the standard of reference for tumor detection and evaluation of treatment response according to Lugano criteria. Sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy of WB DW-MRI at baseline were calculated, and the 95% confidence intervals were estimated by using the Clopper-Pearson (exact) method; changes in tumor SUVs and ADC were compared using a Mann-Whitney U test. Agreement between reviewers was assessed with a Cohen's weighted kappa coefficient. Analyses were conducted using SAS software version 9.4., Results: Agreement between reviewers was perfect (kappa coefficient = 1) for all analyzed regions but spine and neck (kappa coefficient = 0.89 and 0.83, respectively) for 2-[ 18 F]FDG PET images, and abdomen and pelvis (kappa coefficient = 0.65 and 0.88, respectively) for WB DW-MRI. Sensitivity and specificity were 95.5% and 100% for WB DW-MRI compared to 2-[ 18 F]FDG PET. Pre to post-treatment changes in SUV ratio and ADC mean were inversely correlated for all lesions (r: -0.27, p = 0·06) and significantly different between responders and non-responders to chemotherapy (p = 0.0006 and p = 0·003 for SUV ratio and ADC mean , respectively)., Conclusion: Our study showed that WB DW-MRI has similar accuracy to 2-[ 18 F]FDG PET for staging and treatment monitoring of LCH in children. While 2-[ 18 F]FDG PET remains an approved radiological examination for assessing metabolically active disease, WB DW-MRI could be considered as an alternative approach without radiation exposure. The combination of both modalities might have advantages over either approach alone., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Efficient labeling methods for mesenchymal stem cells (MSCs) are crucial for tracking and understanding their behavior in regenerative medicine applications, particularly in cartilage defects. MegaPro nanoparticles have emerged as a potential alternative to ferumoxytol nanoparticles for this purpose. Methods: In this study, we employed mechanoporation to develop an efficient labeling method for MSCs using MegaPro nanoparticles and compared their effectiveness with ferumoxytol nanoparticles in tracking MSCs and chondrogenic pellets. Pig MSCs were labeled with both nanoparticles using a custom-made microfluidic device, and their characteristics were analyzed using various imaging and spectroscopy techniques. The viability and differentiation capacity of labeled MSCs were also assessed. Labeled MSCs and chondrogenic pellets were implanted into pig knee joints and monitored using MRI and histological analysis. Results: MegaPro-labeled MSCs demonstrated shorter T2 relaxation times, higher iron content, and greater nanoparticle uptake compared to ferumoxytol-labeled MSCs, without significantly affecting their viability and differentiation capacity. Post-implantation, MegaPro-labeled MSCs and chondrogenic pellets displayed a strong hypointense signal on MRI with considerably shorter T2* relaxation times compared to adjacent cartilage. The hypointense signal of both MegaPro- and ferumoxytol-labeled chondrogenic pellets decreased over time. Histological evaluations showed regenerated defect areas and proteoglycan formation with no significant differences between the labeled groups. Conclusion: Our study demonstrates that mechanoporation with MegaPro nanoparticles enables efficient MSC labeling without affecting viability or differentiation. MegaPro-labeled cells show enhanced MRI tracking compared to ferumoxytol-labeled cells, emphasizing their potential in clinical stem cell therapies for cartilage defects., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: To provide a holistic and complete comparison of the five most advanced AI models in the augmentation of low-dose 18 F-FDG PET data over the entire dose reduction spectrum., Methods: In this multicenter study, five AI models were investigated for restoring low-count whole-body PET/MRI, covering convolutional benchmarks - U-Net, enhanced deep super-resolution network (EDSR), generative adversarial network (GAN) - and the most cutting-edge image reconstruction transformer models in computer vision to date - Swin transformer image restoration network (SwinIR) and EDSR-ViT (vision transformer). The models were evaluated against six groups of count levels representing the simulated 75%, 50%, 25%, 12.5%, 6.25%, and 1% (extremely ultra-low-count) of the clinical standard 3 MBq/kg 18 F-FDG dose. The comparisons were performed upon two independent cohorts - (1) a primary cohort from Stanford University and (2) a cross-continental external validation cohort from Tübingen University - in order to ensure the findings are generalizable. A total of 476 original count and simulated low-count whole-body PET/MRI scans were incorporated into this analysis., Results: For low-count PET restoration on the primary cohort, the mean structural similarity index (SSIM) scores for dose 6.25% were 0.898 (95% CI, 0.887-0.910) for EDSR, 0.893 (0.881-0.905) for EDSR-ViT, 0.873 (0.859-0.887) for GAN, 0.885 (0.873-0.898) for U-Net, and 0.910 (0.900-0.920) for SwinIR. In continuation, SwinIR and U-Net's performances were also discreetly evaluated at each simulated radiotracer dose levels. Using the primary Stanford cohort, the mean diagnostic image quality (DIQ; 5-point Likert scale) scores of SwinIR restoration were 5 (SD, 0) for dose 75%, 4.50 (0.535) for dose 50%, 3.75 (0.463) for dose 25%, 3.25 (0.463) for dose 12.5%, 4 (0.926) for dose 6.25%, and 2.5 (0.534) for dose 1%., Conclusion: Compared to low-count PET images, with near-to or nondiagnostic images at higher dose reduction levels (up to 6.25%), both SwinIR and U-Net significantly improve the diagnostic quality of PET images. A radiotracer dose reduction to 1% of the current clinical standard radiotracer dose is out of scope for current AI techniques., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Ferumoxytol is an ultrasmall iron oxide nanoparticle that was originally approved by the FDA in 2009 for IV treatment of iron deficiency in adults with chronic kidney disease. Subsequently, its off-label use as an MRI contrast agent increased in clinical practice, particularly in pediatric patients in North America. Unlike conventional MRI contrast agents that are based on the rare earth metal gadolinium (gadolinium-based contrast agents), ferumoxytol is biodegradable and carries no potential risk of nephrogenic systemic fibrosis. At FDA-approved doses, ferumoxytol shows no long-term tissue retention in patients with intact iron metabolism. Ferumoxytol provides unique MRI properties, including long-lasting vascular retention (facilitating high-quality vascular imaging) and retention in reticuloendothelial system tissues, thereby supporting a variety of applications beyond those possible with gadolinium-based contrast agents (GBCAs). This Clinical Perspective describes clinical and early translational applications of ferumoxytol-enhanced MRI in children and young adults through off-label use in a variety of settings, including vascular, cardiac, and cancer imaging, drawing on the institutional experience of the authors. In addition, we describe current advances in pre-clinical and clinical research using ferumoxytol in cellular and molecular imaging as well as the use of ferumoxytol as a novel potential cancer therapeutic agent.

Providing method descriptions that are more detailed than currently available in typical peer reviewed journals has been identified as an actionable area for improvement. In the biochemical and cell biology space, this need has been met through the creation of new journals focused on detailed protocols and materials sourcing. However, this format is not well suited for capturing instrument validation, detailed imaging protocols, and extensive statistical analysis. Furthermore, the need for additional information must be counterbalanced by the additional time burden placed upon researchers who may be already overtasked. To address these competing issues, this white paper describes protocol templates for positron emission tomography (PET), X-ray computed tomography (CT), and magnetic resonance imaging (MRI) that can be leveraged by the broad community of quantitative imaging experts to write and self-publish protocols in protocols.io. Similar to the Structured Transparent Accessible Reproducible (STAR) or Journal of Visualized Experiments (JoVE) articles, authors are encouraged to publish peer reviewed papers and then to submit more detailed experimental protocols using this template to the online resource. Such protocols should be easy to use, readily accessible, readily searchable, considered open access, enable community feedback, editable, and citable by the author.

The availability of high-fidelity animal models for oncology research has grown enormously in recent years, enabling preclinical studies relevant to prevention, diagnosis, and treatment of cancer to be undertaken. This has led to increased opportunities to conduct co-clinical trials, which are studies on patients that are carried out parallel to or sequentially with animal models of cancer that mirror the biology of the patients' tumors. Patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM) are considered to be the models that best represent human disease and have high translational value. Notably, one element of co-clinical trials that still needs significant optimization is quantitative imaging. The National Cancer Institute has organized a Co-Clinical Imaging Resource Program (CIRP) network to establish best practices for co-clinical imaging and to optimize translational quantitative imaging methodologies. This overview describes the ten co-clinical trials of investigators from eleven institutions who are currently supported by the CIRP initiative and are members of the Animal Models and Co-clinical Trials (AMCT) Working Group. Each team describes their corresponding clinical trial, type of cancer targeted, rationale for choice of animal models, therapy, and imaging modalities. The strengths and weaknesses of the co-clinical trial design and the challenges encountered are considered. The rich research resources generated by the members of the AMCT Working Group will benefit the broad research community and improve the quality and translational impact of imaging in co-clinical trials.

Rationale: As a cancer, Glioblastoma (GBM) is a highly lethal and difficult-to-treat. With the aim of improving therapies to GBM, we developed novel and target-specific theranostic nanoparticles (TNPs) that can be selectively cleaved by cathepsin B (Cat B) to release the potent toxin monomethyl auristatin E (MMAE). Methods: We synthesized TNPs composed of a ferumoxytol-based nanoparticle carrier and a peptide prodrug with a Cat-B-responsive linker and the tubulin inhibitor MMAE. We hypothesized that intratumoral Cat B can cleave our TNPs and release MMAE to kill GBM cells. The ferumoxytol core enables in vivo drug tracking with magnetic resonance imaging (MRI). We incubated U87-MG GBM cells with TNPs or ferumoxytol and evaluated the TNP content in the cells with transmission electron microscopy and Prussian blue staining. In addition, we stereotaxically implanted 6- to 8-week-old nude mice with U87-MG with U87-MG GBM cells that express a fusion protein of Green Fluorescence Protein and firefly Luciferase (U87-MG/GFP-fLuc). We then treated the animals with an intravenous dose of TNPs (25 mg/kg of ferumoxytol, 0.3 mg/kg of MMAE) or control. We also evaluated the combination of TNP treatment with radiation therapy. We performed MRI before and after TNP injection. We compared the results for tumor and normal brain tissue between the TNP and control groups. We also monitored tumor growth for a period of 21 days. Results: We successfully synthesized TNPs with a hydrodynamic size of 41 ± 5 nm and a zeta potential of 6 ± 3 mV. TNP-treated cells demonstrated a significantly higher iron content than ferumoxytol-treated cells (98 ± 1% vs. 3 ± 1% of cells were iron-positive, respectively). We also found significantly fewer live attached cells in the TNP-treated group (3.8 ± 2.0 px 2 ) than in the ferumoxytol-treated group (80.0 ± 14.5 px 2 , p < 0001). In vivo MRI studies demonstrated a decline in the tumor signal after TNP (T 2 = 28 ms) but not control (T 2 = 32 ms) injections. When TNP injection was combined with radiation therapy, the tumor signals dropped further (T 2 = 24 ms). The combination therapy of radiation therapy and TNPs extended the median survival from 14.5 days for the control group to 45 days for the combination therapy group. Conclusion: The new cleavable TNPs reported in this work accumulate in GBM, cause tumor cell death, and have synergistic effects with radiation therapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Integrated 2-deoxy-2-[fluorine-18]fluoro-D-glucose ( 18 F-FDG) positron emission tomography (PET)/magnetic resonance (MR) imaging can provide "one stop" local tumor and whole-body staging in one session, thereby streamlining imaging evaluations and avoiding duplicate anesthesia in young children. 18 F-FDG PET/MR scans have the benefit of lower radiation, superior soft tissue contrast, and increased patient convenience compared to 18 F-FDG PET/computerized tomography scans. This article reviews the 18 F-FDG PET/MR imaging technique, reporting requirements, and imaging characteristics of the most common pediatric bone tumors, including osteosarcoma, Ewing sarcoma, primary bone lymphoma, bone and bone marrow metastases, and Langerhans cell histiocytosis., (© 2022. The Author(s), under exclusive licence to International Skeletal Society (ISS).)

Purpose To evaluate if ferumoxytol can improve the detection of bone marrow metastases at diffusion-weighted (DW) MRI in pediatric and young adult patients with cancer. Materials and Methods In this secondary analysis of a prospective institutional review board-approved study (ClinicalTrials.gov identifier NCT01542879), 26 children and young adults (age range: 2-25 years; 18 males) underwent unenhanced or ferumoxytol-enhanced whole-body DW MRI between 2015 and 2020. Two reviewers determined the presence of bone marrow metastases using a Likert scale. One additional reviewer measured signal-to-noise ratios (SNRs) and tumor-to-bone marrow contrast. Fluorine 18 ( 18 F) fluorodeoxyglucose (FDG) PET and follow-up chest CT, abdominal and pelvic CT, and standard (non-ferumoxytol enhanced) MRI served as the reference standard. Results of different experimental groups were compared using generalized estimation equations, Wilcoxon rank sum test, and Wilcoxon signed rank test. Results The SNR of normal bone marrow was significantly lower at ferumoxytol-enhanced MRI compared with unenhanced MRI at baseline (21.380 ± 19.878 vs 102.621 ± 94.346, respectively; P = .03) and after chemotherapy (20.026 ± 7.664 vs 54.110 ± 48.022, respectively; P = .006). This led to an increased tumor-to-marrow contrast on ferumoxytol-enhanced MRI scans compared with unenhanced MRI scans at baseline (1397.474 ± 938.576 vs 665.364 ± 440.576, respectively; P = .07) and after chemotherapy (1099.205 ± 864.604 vs 500.758 ± 439.975, respectively; P = .007). Accordingly, the sensitivity and diagnostic accuracy for detecting bone marrow metastases were 96% (94 of 98) and 99% (293 of 297), respectively, with the use of ferumoxytol-enhanced MRI compared with 83% (106 of 127) and 95% (369 of 390) with the use of unenhanced MRI. Conclusion Use of ferumoxytol helped improve the detection of bone marrow metastases in children and young adults with cancer. Keywords: Pediatrics, Molecular Imaging-Cancer, Molecular Imaging-Nanoparticles, MR-Diffusion Weighted Imaging, MR Imaging, Skeletal-Appendicular, Skeletal-Axial, Bone Marrow, Comparative Studies, Cancer Imaging, Ferumoxytol, USPIO © RSNA, 2023 ClinicalTrials.gov registration no. NCT01542879 See also the commentary by Holter-Chakrabarty and Glover in this issue.

The purpose of our study was to investigate if vascular injury in immature epiphyses affects cartilage repair outcomes of matrix-associated stem cell implants (MASI). Porcine bone marrow mesenchymal stromal stem cells (BMSCs) suspended in a fibrin glue scaffold were implanted into 24 full-thickness cartilage defects (5 mm ø) of the bilateral distal femur of six Göttingen minipigs (n = 12 defects in 6 knee joints of 3 immature pigs; age 3.5-4 months; n = 12 defects in 6 knee joints of 3 mature control pigs; age, 21-28 months). All pigs underwent magnetic resonance imaging (MRI) at 2, 4, 12 (n = 24 defects), and 24 weeks (n = 12 defects). After the last imaging study, pigs were sacrificed, joints explanted and evaluated with VEGF, H&E, van Gieson, Mallory, and Safranin O stains. Results of mature and immature cartilage groups were compared using the Wilcoxon signed-rank test. Quantitative scores for subchondral edema at 2 weeks were correlated with quantitative scores for cartilage repair (MOCART score and ICRS score) at 12 weeks as well as Pineda scores at end of the study, using linear regression analysis. On serial MRIs, mature joints demonstrated progressive healing of cartilage defects while immature joints demonstrated incomplete healing and damage of the subchondral bone. The MOCART score at 12 weeks was significantly higher for mature joints (79.583 ± 7.216) compared to immature joints (30.416 ± 10.543, p = 0.002). Immature cartilage demonstrated abundant microvessels while mature cartilage did not contain microvessels. Accordingly, cartilage defects in immature joints showed a significantly higher number of disrupted microvessels, subchondral edema, and angiogenesis compared to mature cartilage. Quantitative scores for subchondral edema at 2 weeks were negatively correlated with MOCART scores (r =  - 0.861) and ICRS scores (r =  - 0.901) at 12 weeks and positively correlated with Pineda scores at the end of the study (r = 0.782). Injury of epiphyseal blood vessels in immature joints leads to subchondral bone defects and limits cartilage repair after MASI., (© 2022. The Author(s).)

Objectives: To compare the diagnostic accuracy of 2-[ 18 F]fluoro-2-deoxy-D-glucose-enhanced positron emission tomography (2-[ 18 F]FDG-PET) and diffusion-weighted magnetic resonance imaging (DW-MRI) for the detection of bone marrow metastases in children and young adults with solid malignancies., Methods: In this cross-sectional single-center institutional review board-approved study, we investigated twenty-three children and young adults (mean age, 16.8 years ± 5.1 [standard deviation]; age range, 7-25 years; 16 males, 7 females) with 925 bone marrow metastases who underwent 66 simultaneous 2-[ 18 F]FDG-PET and DW-MRI scans including 23 baseline scans and 43 follow-up scans after chemotherapy between May 2015 and July 2020. Four reviewers evaluated all foci of bone marrow metastasis on 2-[ 18 F]FDG-PET and DW-MRI to assess concordance and measured the tumor-to-bone marrow contrast. Results were assessed with a one-sample Wilcoxon test and generalized estimation equation. Bone marrow biopsies and follow-up imaging served as the standard of reference., Results: The reviewers detected 884 (884/925, 95.5%) bone marrow metastases on 2-[ 18 F]FDG-PET and 893 (893/925, 96.5%) bone marrow metastases on DW-MRI. We found different "blind spots" for 2-[ 18 F]FDG-PET and MRI: 2-[ 18 F]FDG-PET missed subcentimeter lesions while DW-MRI missed lesions in small bones. Sensitivity and specificity were 91.0% and 100% for 18 F-FDG-PET, 89.1% and 100.0% for DW-MRI, and 100.0% and 100.0% for combined modalities, respectively. The diagnostic accuracy of combined 2-[ 18 F]FDG-PET/MRI (100.0%) was significantly higher compared to either 2-[ 18 F]FDG-PET (96.9%, p < 0.001) or DW-MRI (96.3%, p < 0.001)., Conclusions: Both 2-[ 18 F]FDG-PET and DW-MRI can miss bone marrow metastases. The combination of both imaging techniques detected significantly more lesions than either technique alone., Key Points: • DW-MRI and 2-[ 18 F]FDG-PET have different strengths and limitations for the detection of bone marrow metastases in children and young adults with solid tumors. • Both modalities can miss bone marrow metastases, although the "blind spot" of each modality is different. • A combined PET/MR imaging approach will achieve maximum sensitivity and specificity for the detection of bone marrow metastases in children with solid tumors., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Purpose: Current checkpoint inhibitor immunotherapy strategies in glioblastoma are challenged by mechanisms of resistance including an immunosuppressive tumor microenvironment. T cell immunoglobulin domain and mucin domain 3 (TIM3) is a late-phase checkpoint receptor traditionally associated with T cell exhaustion. We apply fluorescent imaging techniques to explore feasibility of in vivo visualization of the immune state in a glioblastoma mouse model., Procedures: TIM3 monoclonal antibody was conjugated to a near-infrared fluorescent dye, IRDye-800CW (800CW). The TIM3 experimental conjugate and isotype control were assessed for specificity with immunofluorescent staining and flow cytometry in murine cell lines (GL261 glioma and RAW264.7 macrophages). C57BL/6 mice with orthotopically implanted GL261 cells were imaged in vivo over 4 days after intravenous TIM3-800CW injection to assess tumor-specific uptake. Cell-specific uptake was then assessed on histologic sections., Results: The experimental TIM3-800CW, but not its isotype control, bound to RAW264.7 macrophages in vitro. Specificity to RAW264.7 macrophages and not GL261 tumor cells was quantitatively confirmed with the corresponding clone of TIM3 on flow cytometry. In vivo fluorescence imaging of the 800CW signal was localized to the intracranial tumor and significantly higher for the TIM3-800CW cohort, relative to non-targeting isotype control, immediately after tail vein injection and for up to 48 h after injection. Resected organs of tumor bearing mice showed significantly higher uptake in the liver and spleen. TIM3-800CW was seen to co-stain with CD3 (13%), CD11b (29%), and CD206 (26%)., Conclusions: We propose fluorescent imaging of immune cell imaging as a potential strategy for monitoring and localizing immunologically relevant foci in the setting of brain tumors. Alternative markers and target validation will further clarify the temporal relationship of immunosuppressive effector cells throughout glioma resistance., (© 2021. World Molecular Imaging Society.)

Regenerative medicine uses the patient own stem cells to regenerate damaged tissues. Molecular imaging techniques are commonly used to image the transplanted cells, either right after surgery or at a later time. However, few techniques are fast or straightforward enough to label cells intraoperatively. Adipose tissue-derived stem cells (ADSCs) were harvested from knee joints of minipigs. The cells were labeled with PET contrast agent by flowing mechanoporation using a microfluidic device. While flowing through a series of microchannels, cells are compressed repeatedly by micro-ridges, which open transient pores in their membranes and induce convective transport, intended to facilitate the transport of 68 Ga-labeled and lipid-coated mesoporous nanoparticles (MSNs) into the cells. This process enables cells to be labeled in a matter of seconds. Cells labeled with this approach were then implanted into cartilage defects, and the implant was imaged using positron emission tomography (PET) post-surgery. The microfluidic device can efficiently label millions of cells with 68 Ga-labeled MSNs in as little as 15 min. The method achieved labeling efficiency greater than 5 Bq/cell on average, comparable to 30 min-long passive co-incubation with 68 Ga-MSNs, but with improved biocompatibility due to the reduced exposure to ionizing radiation. Labeling time could also be accelerated by increasing throughput through more parallel channels. Finally, as a proof of concept, ADSCs were labeled with 68 Ga-MSNs and quantitatively assessed using clinical PET/MR in a mock transplant operation in pig knee joints. MSN-assisted mechanoporation is a rapid, effective and straightforward approach to label cells with 68 Ga. Given its high efficiency, this labeling method can be used to track small cells populations without significant effects on viability. The system is applicable to a variety of cell tracking studies for cancer therapy, regenerative therapy, and immunotherapy., (© 2022. The Author(s).)

Metastatic osteosarcoma has a poor prognosis with a 2-y, event-free survival rate of ∼15 to 20%, highlighting the need for the advancement of efficacious therapeutics. Chimeric antigen receptor (CAR) T-cell therapy is a potent strategy for eliminating tumors by harnessing the immune system. However, clinical trials with CAR T cells in solid tumors have encountered significant challenges and have not yet demonstrated convincing evidence of efficacy for a large number of patients. A major bottleneck for the success of CAR T-cell therapy is our inability to monitor the accumulation of the CAR T cells in the tumor with clinical-imaging techniques. To address this, we developed a clinically translatable approach for labeling CAR T cells with iron oxide nanoparticles, which enabled the noninvasive detection of the iron-labeled T cells with magnetic resonance imaging (MRI), photoacoustic imaging (PAT), and magnetic particle imaging (MPI). Using a custom-made microfluidics device for T-cell labeling by mechanoporation, we achieved significant nanoparticle uptake in the CAR T cells, while preserving T-cell proliferation, viability, and function. Multimodal MRI, PAT, and MPI demonstrated homing of the T cells to osteosarcomas and off-target sites in animals administered with T cells labeled with the iron oxide nanoparticles, while T cells were not visualized in animals infused with unlabeled cells. This study details the successful labeling of CAR T cells with ferumoxytol, thereby paving the way for monitoring CAR T cells in solid tumors., Competing Interests: Competing interest statement: R.G.M. is a consultant for Lyell Immunopharma, Illumina Radiopharmaceuticals, and GammaDelta Therapeutics. T.S. is a cofounder of CellFE and a consultant for Heat Bio., (Copyright © 2022 the Author(s). Published by PNAS.)

Gadolinium chelates have been used as standard contrast agents for clinical MRI for several decades. However, several investigators recently reported that rare Earth metals such as gadolinium are deposited in the brain for months or years. This is particularly concerning for children, whose developing brain is more vulnerable to exogenous toxins compared to adults. Therefore, a search is under way for alternative MR imaging biomarkers. The United States Food and Drug Administration (FDA)-approved iron supplement ferumoxytol can solve this unmet clinical need: ferumoxytol consists of iron oxide nanoparticles that can be detected with MRI and provide significant T1- and T2-signal enhancement of vessels and soft tissues. Several investigators including our research group have started to use ferumoxytol off-label as a new contrast agent for MRI. This article reviews the existing literature on the biodistribution of ferumoxytol in children and compares the diagnostic accuracy of ferumoxytol- and gadolinium-chelate-enhanced MRI. Iron oxide nanoparticles represent a promising new class of contrast agents for pediatric MRI that can be metabolized and are not deposited in the brain., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The disialoganglioside GD2 is overexpressed on several solid tumors, and monoclonal antibodies targeting GD2 have substantially improved outcomes for children with high-risk neuroblastoma. However, approximately 40% of patients with neuroblastoma still relapse, and anti-GD2 has not mediated significant clinical activity in any other GD2 + malignancy. Macrophages are important mediators of anti-tumor immunity, but tumors resist macrophage phagocytosis through expression of the checkpoint molecule CD47, a so-called 'Don't eat me' signal. In this study, we establish potent synergy for the combination of anti-GD2 and anti-CD47 in syngeneic and xenograft mouse models of neuroblastoma, where the combination eradicates tumors, as well as osteosarcoma and small-cell lung cancer, where the combination significantly reduces tumor burden and extends survival. This synergy is driven by two GD2-specific factors that reorient the balance of macrophage activity. Ligation of GD2 on tumor cells (a) causes upregulation of surface calreticulin, a pro-phagocytic 'Eat me' signal that primes cells for removal and (b) interrupts the interaction of GD2 with its newly identified ligand, the inhibitory immunoreceptor Siglec-7. This work credentials the combination of anti-GD2 and anti-CD47 for clinical translation and suggests that CD47 blockade will be most efficacious in combination with monoclonal antibodies that alter additional pro- and anti-phagocytic signals within the tumor microenvironment., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Accurate staging and re-staging of cancer in children is crucial for patient management. Currently, children with a newly diagnosed cancer must undergo a series of imaging tests, which are stressful, time-consuming, partially redundant, expensive, and can require repetitive anesthesia. New approaches for pediatric cancer staging can evaluate the primary tumor and metastases in a single session. However, traditional one-stop imaging tests, such as CT and positron emission tomography (PET)/CT, are associated with considerable radiation exposure. This is particularly concerning for children because they are more sensitive to ionizing radiation than adults and they live long enough to experience secondary cancers later in life. In this review article we discuss child-tailored imaging tests for tumor detection and therapy response assessment - tests that can be obtained with substantially reduced radiation exposure compared to traditional CT and PET/CT scans. This includes diffusion-weighted imaging (DWI)/MRI and integrated [F-18]2-fluoro-2-deoxyglucose ( 18 F-FDG) PET/MRI scans. While several investigators have compared the value of DWI/MRI and 18 F-FDG PET/MRI for staging pediatric cancer, the value of these novel imaging technologies for cancer therapy monitoring has received surprisingly little attention. In this article, we share our experiences and review existing literature on this subject., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The diagnosis of joint infiltration by a malignant bone tumor affects surgical management. The specificity of standard magnetic resonance imaging (MRI) for diagnosing joint infiltration is limited. During our MRI evaluations with ferumoxytol nanoparticles of pediatric and young adult patients with bone sarcomas, we observed a surprising marked T1 enhancement of joint and pleural effusions in some patients but not in others., Objective: To evaluate if nanoparticle extravasation differed between joints and pleura with and without tumor infiltration., Materials and Methods: We retrospectively identified 15 pediatric and young adult patients (mean age: 16±4 years) with bone sarcomas who underwent 18 MRI scans at 1 h (n=7) or 24 h (n=11) after intravenous ferumoxytol infusion. Twelve patients also received a gadolinium-enhanced MRI. We determined tumor invasion into the joint or pleural space based on histology (n=11) and imaging findings (n=4). We compared the signal-to-noise ratios (SNR) and contrast-to-noise ratios (CNR) of the joint or pleural fluid for tumors with and without invasion using a Mann-Whitney U test., Results: MRI scans 24 h after intravenous ferumoxytol infusion demonstrated a positive T1 enhancement of the effusion in all joints and pleural spaces with tumor infiltration and no joint or pleural space without infiltration. Corresponding SNR (P=0.004) and CNR (P=0.004) values were significantly higher for joints and pleural spaces with tumor infiltration than without. By contrast, unenhanced MRI, gadolinium-enhanced MRI and 1-h post-contrast ferumoxytol MRI did not show any enhancement of the joint or pleural effusion, with or without tumor infiltration., Conclusion: This pilot study suggests that 24-h post-contrast ferumoxytol MRI scans can noninvasively differentiate between joints with and without tumor infiltration., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)