Nanoparticle delivery to glioblastoma is limited by the blood-brain barrier (BBB), which restricts the transport of diagnostic and therapeutic agents into tumor tissue. Microbubble-mediated focused ultrasound (FUS) can transiently increase BBB permeability and enhance localized delivery of molecular probes and drugs. We tested whether MRI-guided microbubble-assisted FUS at 650 kHz enables spatially controlled and quantitatively measurable delivery of the FDA-approved ferumoxytol (FMX), an iron oxide nanoparticle formulation. Acoustic simulations were employed to quantify transcranial pressure fields and assess pressure-dependent BBB opening at a clinically relevant frequency and were experimentally validated in healthy mice. In mice bearing orthotopic U87 glioblastoma, MRI-guided microbubble-assisted FUS was focally applied to the tumor region, with intravenously administered Definity microbubbles mediating transient BBB opening, followed by intravenous injection of fluorescein-labeled FMX. Nanoparticle accumulation was quantified using in vivo MRI and postmortem fluorescence imaging. Post-contrast tumor T2 relaxation times were 33.14 ms in the FMX group and 22.47 ms in the FMX + FUS group. Tumor transverse relaxation rate change showed a 2.6-fold increase under FUS conditions relative to the non-FUS group, demonstrating enhanced nanoparticle transport across a transiently permeabilized BBB. Pressure thresholds were identified for FMX delivery to normal brain versus tumor tissue, with a lower estimated threshold in tumor tissue than in healthy brain (0.224 MPa vs. 0.265 MPa), highlighting a pressure window for selective nanoparticle transport. Histopathological evaluation of H&E-stained normal brain and tumor sections showed no significant FUS-associated increase in detectable acute structural tissue damage. Our findings establish a quantitative and clinically translatable framework for spatially controlled FUS-enhanced delivery of clinically relevant nanoparticle formulations to brain tumors, advancing targeted delivery strategies for neuro-oncologic applications.

Emerging metallic radionuclides are expanding theranostic capabilities in nuclear medicine by improving diagnostic sensitivity, enabling dosimetry, and matched theranostic approaches. 149Tb, 44Sc, 52Mn, 203Pb, and 55Co offer distinct nuclear decay properties, including extended half-lives, variable positron emissions, and prompt γ-photons that may influence quantitative imaging performance. Cyclotron and generator routes integrating enriched targets and optimized separations support clinical-scale supply, while advances in chelation chemistry improve in vivo stability and imaging performance. Preclinical and early clinical data demonstrate that 149Tb provides intrinsic α-therapy and PET imaging capability for theranostic use, 44Sc enables extended imaging relative to 68Ga, supporting delayed imaging and improved tumor-to-background contrast for peptide-based radiopharmaceuticals and theranostic applications. 52Mn supports prolonged biological tracking for antibody- and engineered-protein-targeted studies, whereas 203Pb serves as a diagnostic surrogate for 212Pb based α-therapy (via 212Bi). 55Co PET imaging supports the development and evaluation of 58mCo Auger electron therapy. Current challenges include limited global availability of highly enriched targets, management of long-lived radioactive by-products, and the need for standardized dosimetry and regulatory pathways to ensure reproducibility and safety. Ongoing developments in automated target handling, optimized separations, next-generation chelators, and harmonized regulation may facilitate broader clinical translation.

Targeting CD47 with monoclonal antibody (mAb) therapy activates tumor-associated macrophages (TAMs). Quantitative imaging methods are important for identifying responders to this novel immunotherapy. The purpose of our study was to investigate whether the metabolic activity of osteosarcomas on 18F-FDG PET/CT changes after CD47 mAb treatment. Twenty female BALB/c mice with intratibial murine K7M2 osteosarcomas, twenty female NOD scid gamma (NSG) mice with intratibial human 143B tumors, and twenty male NSG mice with intratibial human MG63.3 tumors were treated with either phosphate-buffered saline (PBS) or murine/human CD47 mAb (n = 10 per arm) and underwent either 18F-FDG PET/CT or ferumoxytol-enhanced MRI (n = 5 per group). Differences in tumor metabolic activity (%ID/g max), tumor T2* relaxation times, TAM (%F4/80), and M1 macrophage polarization (%CD80+) between PBS and CD47 mAb-treated mice were estimated from linear regression. The tumor %ID/g max of CD47 mAb-treated K7M2 tumors (6.58 ± 2.42) was not significantly different compared to PBS-treated K7M2 tumors (8.04 ± 2.91; p = 0.17). Similarly, the tumor %ID/g max of CD47 mAb-treated 143B tumors (9.12 ± 1.68) and MG63.3 tumors (5.44 ± 1.99) were not significantly different compared to PBS-treated 143B tumors (9.38 ±  2.32; p = 0.32 ) and MG63.3 tumors (6.02 ±  0.63, p = 0.79 ). By comparison, K7M2 tumors, 143B tumors, and MG63.3 tumors all demonstrated significantly shorter T2* relaxation times after CD47 mAb treatment compared to PBS treatment (all p < 0.001). All tumors exhibited significantly higher TAM (%F4/80+) and M1 macrophage polarization (%CD80+) after CD47 mAb treatment compared to PBS treatment (all p < 0.05). The metabolic activity of osteosarcomas on 18F-FDG PET/CT does not show significant changes after CD47 mAb treatment. This lowers the risk of observing pseudoprogression and misinterpreting drug-induced inflammation, simplifying routine clinical scan interpretation.

CAR T-cell therapy is a transformative immunotherapy for pediatric patients with relapsed or refractory malignancies. Imaging plays a crucial role in evaluating treatment efficacy and detecting complications. This review provides time-specific guidance for radiologists on the imaging findings before and after CAR T-cell infusion and highlights how imaging supports clinical decision-making across the treatment course. Pre-treatment imaging at baseline focuses on ruling out active infection and quantifying residual tumor burden. In addition, quantitative imaging biomarkers can predict tumor response and toxicity risk. Between day 0–28 after CAR T-cell infusion, imaging is primarily performed to detect side effects, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). At day + 28, imaging provides early assessment of tumor response. Radiologists must recognize atypical immune-related response patterns at this time, including pseudoprogression and, less commonly, hyperprogression. Beyond day 28, imaging monitors for late side effects and infections, while also documenting ongoing tumor response or recurrence. Familiarity with these time-specific imaging patterns and pitfalls, coupled with knowledge of quantitative biomarkers, enables radiologists to differentiate toxicity from therapeutic effect, avoid misclassification of early immune-related changes, and optimize outcomes in pediatric CAR T-cell therapy.

RATIONALE AND OBJECTIVES:To correlate quantitative measures of tumor cell density, derived from diffusion-weighted magnetic resonance imaging (MRI), with quantitative measures of tumor glucose metabolism, derived from 18F-FDG positron emission tomography (PET), and post-induction event-free survival (EFS) in patients with metastatic Ewing sarcoma. MATERIALS AND METHODS:We performed a secondary review of 21 patients (mean age 14.1 years ±4.67, 12 females) with metastatic Ewing sarcoma who were enrolled in a prospective, multicenter phase III clinical trial by the Children's Oncology Group (AEWS1221) and underwent paired diffusion-weighted MRI and 18F-FDG PET scans at baseline and post induction chemotherapy (after 6 cycles). Tumor size, apparent diffusion coefficient (ADC)mean and ADCmin (whole tumor, viable, and necrotic portions), and standardized uptake values (SUVmax) were measured. Pearson's correlation coefficient was used to assess relationships between continuous imaging biomarkers. RESULTS:Baseline ADCmean of the viable tumor inversely correlated with SUVmax (R = -0.51, p = 0.022). After induction, SUVmax inversely correlated with whole tumor ADCmin (R = -0.59, p = 0.028) but not with viable tumor ADCmean (R = -0.15, p = 0.62). Both whole tumor ADCmin and viable tumor ADCmean post-induction correlated with tumor volume changes (R = -0.56, p = 0.008; R = -0.5, p = 0.022). None of these biomarkers were associated with EFS risk. CONCLUSION:Baseline ADCmean (excluding necrosis) may serve as a surrogate for SUVmax, while post-induction ADCmin correlates with metabolic activity but not survival outcomes. Further studies are needed to validate these findings.

Despite robust preclinical activity, CD47-targeting agents demonstrate limited single-agent efficacy in osteosarcomas. The purpose of our study was to investigate whether tumor size at baseline affects tumor-associated macrophage (TAM) response to CD47 mAb, as measured by ferumoxytol-MRI. Thirty female NOD SCID gamma mice and thirty BALB/c mice with small, medium-sized, and large 143B osteosarcoma xenografts or murine K7M2 tumors were treated with either CD47 mAb or PBS. All mice underwent MRI scans at baseline, one week after treatment, and after intravenous infusion of ferumoxytol nanoparticles. We measured tumor T2* relaxation times as a quantitative measure of nanoparticle retention in activated TAMs. Tumor ΔT2* was calculated as the difference between T2* post-treatment pre-contrast and T2* post-treatment post-contrast to quantify ferumoxytol enhancement. T2* and ΔT2* values were compared between treatment groups using regression models including treatment, tumor size, and their interaction. Histology served as a standard of reference. At baseline, tumors in CD47 mAb- and PBS-treated mice demonstrated no significant differences in T2* relaxation time, regardless of tumor size (all p > 0.05). After CD47 mAb therapy and ferumoxytol infusion, tumors treated with CD47 mAb demonstrated significantly shorter T2* relaxation times compared with PBS-treated tumors (all p < 0.001). The tumor ΔT2* enhancement was significantly higher in small tumors compared with large tumors (all p < 0.001), indicating higher nanoparticle accumulation in small tumors after CD47 blockade. Histopathology showed a significantly higher F4/80+CD80+ TAM staining in CD47 mAb-treated small tumors compared with large tumors (all p < 0.05). In conclusion, tumor size at baseline affects TAM response to CD47 mAb. Smaller osteosarcomas exhibit a more pronounced TAM response to CD47 mAb therapy compared with larger tumors.

BackgroundAccurate staging of Hodgkin lymphoma in children is important for selecting appropriate therapies. However, evaluation of Ann Arbor staging criteria on whole-body 18F-FDG PET scans is time-consuming and subject to reader-dependent variability.ObjectiveTo determine if a novel computer-aided staging tool can improve the time-efficiency and accuracy of Ann Arbor staging.Methods18F-FDG PET/MRI scans of fifty-six pediatric patients were divided into two groups with matched Ann-Arbor stages. Group 1 was staged via traditional inspection and Group 2 was staged with a newly developed web-based staging tool by one radiology resident, four radiologists and two nuclear medicine physicians. An additional radiologist and nuclear medicine physician jointly established the reference standard. The time to generate the Ann Arbor score was compared between group 1 and 2 with the Wilcoxon Rank-Sum test, and agreement with the reference standard was assessed with Cohen's kappa analysis. In addition, staging time was correlated with reader experience level, measured as the number of PET cases interpreted per year, using linear regression analysis.ResultUse of the tool significantly reduced Ann Arbor staging time (10.8 ± 6.33 min) compared to traditional staging without the tool (13.87 ± 8.16 min; p = 0.001). The greatest reduction in staging time was observed for the radiology resident (17.63 ± 2.3 min with the tool and 21.5 ± 3.3 without the tool), followed by radiologists (13.63 ± 2.5 min with the tool and 18.03 ± 2.6 without the tool), while no significant change was observed for nuclear medicine physicians (1.45 ± 0.82 min with the tool and 1.39 ± 1.12 without the tool). Agreement with the reference standard improved with tool assistance (κ = 0.616) compared to traditional staging without the tool (κ = 0.945 with the tool). Linear regression demonstrated a significant inverse association between reader experience and time saved using the tool (β = −0.812, p < 0.001; R² = 0.66), indicating greater benefit for less experienced readers.ConclusionThe computer-aided staging tool significantly improved time-efficiency and accuracy of Ann Arbor staging, especially for less experienced readers. We provide the tool as a freely accessible web resource.

We assessed the performance of a deep convolutional neural network (CNN) in detecting pediatric lymphoma lesions on [18F]FDG-PET/MRI. We evaluated CNN's sensitivity, specificity, percentage agreement, and processing time compared to the interpretations of a pediatric radiologist and a second-year radiology resident. In this retrospective study, a CNN was trained on annotated [18F]FDG-PET/MRI scans from 53 pediatric lymphoma patients and tested on 30 additional scans. The CNN and two human readers recorded the presence of lesions in five anatomical regions. An additional pediatric radiologist and a nuclear medicine physician determined the reference standard. The sensitivity and specificity of the CNN were compared with those of human readers using the McNemar test, and the detection time of the CNN and human readers was compared using the Wilcoxon signed-rank test. The CNN demonstrated higher sensitivity (84.6%) and specificity (93.7%) than the radiology resident (69.2%, P=0.023; 81.5%, P<0.001), but lower than the pediatric radiologist (98.7%, P<0.001; 99.5%, P<0.001). The CNN achieved 83% agreement with the reference standard (95% CI: 79%-87%), higher than the resident's 63% (95% CI: 59%-69%) but lower than the pediatric radiologist's 94% (95% CI: 92%-97%). The median values and interquartile ranges for the time taken (in minutes) were 4 (3, 5) for the CNN, 8 (7, 10) for the pediatric radiologist, and 15 (9, 20) for the radiology resident. The sensitivity, specificity, and percentage agreement of the CNN were higher than those of a radiology resident but lower than those of a pediatric radiologist. The CNN readout was significantly faster compared to both human readers.

and Purpose. Activation of tumor-associated macrophages (TAMs) by CD47 mAb therapy can be monitored with ferumoxytol-enhanced magnetic resonance imaging (MRI). The purpose of our study was to investigate if tumor size at baseline affects TAM response to CD47 mAb, as measured with ferumoxytol-MRI. Thirty female NOD scid gamma (NSG) mice with small-sized (tumor volume = 30 mm3), medium-sized (tumor volume = 500 mm3), and large (tumor volume = 1200 mm3) 143B osteosarcoma xenografts were treated with human CD47 mAb (10 mg/kg, day 1, 3, and 5 for 1 week) or PBS (control group). All mice underwent MRI scans at baseline and at one week after CD47 mAb or sham treatment. Post-treatment scans were obtained before and after intravenous infusion of ferumoxytol nanoparticles (30 Fe mg/kg). We measured tumor T2* relaxation times as a quantitive measure of nanoparticle retention in TAM. The tumor ferumoxytol enhancement, calculated as: ΔT2* = 100 * (T2*precontrast - T2*postcontrast) / T2*precontrast, was compared between experimental groups using exact two-sided Wilcoxon rank-sum tests. Histology served as standard of reference. At baseline, tumors of CD47 mAb and PBS-treated mice demonstrated no significant difference in T2* relaxation time, regardless of tumor size (all p>0.05). After CD47 mAb therapy, tumors treated with CD47 mAb demonstrated significantly shorter T2* relaxation times compared to PBS-treated mice (all p<0.001). The tumor T2* enhancement was significantly higher in small tumors (ΔT2* = 41.3% +/- 2.182%) compared to large tumors (ΔT2* = 2.93% +/- 2.474%; p=0.001), indicating stronger nanoparticle phagocytosis in small sized tumors, apparently due to increased TAM activation. There was not statistically significance difference between T2* relaxation time of small and medium-sized tumors in all time points (all p> 0.05). Histopathological correlations confirmed a significantly higher number of CD80-positive TAMs in small sized tumors after CD47 mAb therapy (61.28% +/- 1.77%) compared to large sized tumors (3.38% +/- 0.81%, p<0.001). Tumor size at baseline affects TAM response to CD47 mAb. Smaller osteosarcomas exhibit a more pronounced TAM response to CD47 mAb therapy compared to larger tumors. Raheleh Roudi, Iryna Vasylkiv, Laura Pisani, Tie Liang, Raya Saab, Heike Daldrup-Link. Impact of baseline tumor size on response to anti-CD47 immunotherapy in an osteosarcoma mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5797.

Senescent cells promote osteoarthritis progression through the secretion of inflammatory mediators. Preclinical studies have identified senescence-associated beta-galactosidase (β-gal) as a biomarker of senescence, but in vivo detection remains challenging. Here, we evaluated whether a β-gal responsive gadolinium (Gd) chelate can non-invasively detect β-gal expressing senescent cells with standard clinical magnetic resonance imaging (MRI) technology in vitro, ex vivo, and in vivo in porcine joints. In vitro studies showed that senescent mesenchymal stromal cells (MSCs) exhibited significant MRI signal enhancement upon incubation with the β-gal responsive Gd-chelate compared to viable control cells. In vivo, intraarticular injection of the probe into pig knee joints revealed its retention and activation by senescent cells in cartilage defects, evidenced by a significant increase in R1 relaxation rate. MRI-based senescent cell detection holds promise for identifying patients amenable to senolytic therapies, tailoring treatment plans, and monitoring therapy response in real-time.

Theranostic nanoparticles (NPs) have been designed for simultaneous therapeutic and diagnostic purposes, thereby enabling personalized cancer therapy and in vivo drug tracking. However, studies thus far have focused on imaging NP tumor accumulation at the macroscopic level and correlating results with ex vivo histology. Limited evidence exists on whether in vivo NP tumor contrast enhancement on magnetic resonance imaging (MRI) correlates with in vivo NP tumor accumulation at the microscopic level. To address this gap, the purpose of our study was to correlate quantitative MRI estimates of NP accumulation with in vivo NP signal quantification as measured through two-photon intravital microscopy (IVM) in an orthotopic murine glioblastoma multiforme model (GBM). To enable multimodal imaging, we designed dual-mode NPs, composed of a carbohydrate-coated magnetic core (Ferumoxytol) as an MRI contrast agent, and a conjugated fluorophore (FITC) for IVM detection. We administered these NPs with or without a conjugated vascular disrupting agent (VDA) to assess its effect on NP delivery to GBM. We correlated in vivo MRI contrast enhancement in tumors, quantified as T2 relaxation time, with IVM fluorescence spatial decay rate. Results demonstrated a significantly lower tumor T2 relaxation time and spatial decay rate in tumors targeted with VDA-conjugated NPs compared to unconjugated NPs. Postmortem histological analyses validated the in vivo observations. The presented multimodal imaging approach enabled a quantitative correlation between MRI contrast enhancement at the macroscopic level and NP accumulation in the tumor microenvironment. These studies lay the groundwork for the precise evaluation of the tumor targeting of theranostic NPs.

Chimeric Antigen Receptor (CAR) T-cell therapy has demonstrated efficacy in children and young adult patients with acute lymphoblastic leukemia (ALL). The purpose of our study was to investigate thymus size changes after CAR T-cell therapy, explore the associated clinical conditions, and assess survival differences of patients who underwent CAR T-cell therapy, we conducted a single-center retrospective study of children and young adult patients who underwent CAR T-cell therapy for ALL between April 2015 and October 2023.We measured the volume of the thymus on pre- and post-CAR T-cell chest CT scans of 20 patients (median [IQR] age, 18[11] years; 11 females). We divided patients into two groups, those who did (group 1) or did not (group 2) demonstrate increase in thymus size after therapy. Clinical and survival data were collected. We used the Wilcoxon signed-rank test or Fisher's exact test for group comparisons and analyzed event-free survival data. Seven of 20 patients (35%, group 1) showed increase in thymus volume (pre- vs. post-CAR T-cell thymus volume; 5.01 [2.18] cm³ vs. 20.87 [19.86] cm³, p = 0.01), while 13 patients (65%, group 2) showed no increase in thymus volume (pre- vs. post-CAR T-cell thymus volume; 3.01 [13.42] cm³ vs. 2.09 [8.34] cm³, p = 0.01). Patients in group 1 were younger (12 [8] years vs. 19[10] years, p = 0.028) and showed a higher rate of event-free survival compared to those in group 2 (p = 0.003). In children and young adults with ALL, increased thymus size after CAR T-cell therapy was associated with younger age and improved clinical outcomes.

The use of whole-body MRI (WBMRI) in children, from infancy to adolescence, has expanded rapidly over the past decade, with increasing uptake and a broadening range of clinical indications. Current indications include screening for presymptomatic lesions in cancer predisposition syndromes; tumor staging in known malignancies; investigating fevers of unknown origin; as well as diagnosing and monitoring rheumatologic diseases, vascular anomalies, and neuromuscular disorders. This AJR Expert Panel Narrative Review aims to offer a comprehensive discussion of WBMRI in pediatric patients, exploring protocols and other technical considerations, clinical indications, implementation challenges and troubleshooting, as well as controversies in widespread adoption, while considering emerging trends and directions. Commonalities and variations in WBMRI protocols across indications and institutions are presented, highlighting the need for greater standardization. Barriers to WBMRI access, particularly in resource-limited settings, are considered, along with potential solutions. The available evidence regarding potential patient benefit from WBMRI across various applications is summarized.

To evaluate brain MRI findings in children and young adults after chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphoid leukemia (B-ALL) and associate results with clinical and neurological symptoms. We reviewed pre- and post-CAR-T cell therapy brain MRIs of B-ALL patients aged 25 years or younger who underwent therapy between April 2015 and October 2023 at a single institution. MRI abnormalities were categorized as no change, exacerbation of preexisting lesion, or newly developed lesion. Clinical CAR-mediated toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) grades, were recorded. Patients were grouped into those with and without ‘exacerbated/new lesion,’ and clinical and neurological symptoms were compared using Fisher’s exact test. Sixteen patients with pre- and post-CAR brain MRIs (median age 16 years [interquartile range, 11–21]; 9 males, 7 females) were included in the analysis. Post-CAR brain abnormalities were observed in 81

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. Senescent cells have complex and important roles in cancer and ageing, but they are quite rare and difficult to characterize in tissues in vivo. In this Expert Recommendation, the SenNet Biomarkers Working Group discusses recent advances in detecting and characterizing cellular senescence and provides recommendations for senescence markers in 14 human and mouse tissues.

High-grade endometrial stromal sarcoma is a rare and aggressive soft tissue tumor characterized by YWHAE::NUTM2A/B translocations, diagnosis at a median of 50-60 years, and a poor prognosis (overall survival 30%-40%). We describe a 16-year-old patient with high-grade endometrial stromal sarcoma and regional nodal and pulmonary metastases who is a long-term survivor after grossly complete tumor resection, intensive chemotherapy, and pelvic radiotherapy. We discovered a previously undescribed YWHAE::NUTM2E translocation in the tumor. Our patient’s favorable outcome suggests that intensive multimodality therapy with curative intent is appropriate for young patients with high-grade endometrial stromal sarcoma and highlights the importance of fertility preservation.

Significant improvements in treatments for children with cancer have resulted in a growing population of childhood cancer survivors who may face long-term adverse outcomes. Here, we aimed to diagnose high-dose methotrexate-induced brain injury on [18F]FDG PET/MRI and correlate the results with cognitive impairment identified by neurocognitive testing in pediatric cancer survivors. Methods: In this prospective, single-center pilot study, 10 children and young adults with sarcoma (n = 5), lymphoma (n = 4), or leukemia (n = 1) underwent dedicated brain [18F]FDG PET/MRI and a 2-h expert neuropsychologic evaluation on the same day, including the Wechsler Abbreviated Scale of Intelligence, second edition, for intellectual functioning; Delis-Kaplan Executive Function System (DKEFS) for executive functioning; and Wide Range Assessment of Memory and Learning, second edition (WRAML), for verbal and visual memory. Using PMOD software, we measured the SUVmean, cortical thickness, mean cerebral blood flow (CBFmean), and mean apparent diffusion coefficient of 3 different cortical regions (prefrontal cortex, cingulate gyrus, and hippocampus) that are routinely involved during the above-specified neurocognitive testing. Standardized scores of different measures were converted to z scores. Pairs of multivariable regression models (one for z scores < 0 and one for z scores > 0) were fitted for each brain region, imaging measure, and test score. Heteroscedasticity regression models were used to account for heterogeneity in variances between brain regions and to adjust for clustering within patients. Results: The regression analysis showed a significant correlation between the SUVmean of the prefrontal cortex and cingulum and DKEFS-sequential tracking (DKEFS-TM4) z scores (P = 0.003 and P = 0.012, respectively). The SUVmean of the hippocampus did not correlate with DKEFS-TM4 z scores (P = 0.111). The SUVmean for any evaluated brain regions did not correlate significantly with WRAML-visual memory (WRAML-VIS) z scores. CBFmean showed a positive correlation with SUVmean (r = 0.56, P = 0.01). The CBFmean of the cingulum, hippocampus, and prefrontal cortex correlated significantly with DKEFS-TM4 (all P < 0.001). In addition, the hippocampal CBFmean correlated significantly with negative WRAML-VIS z scores (P = 0.003). Conclusion: High-dose methotrexate-induced brain injury can manifest as a reduction in glucose metabolism and blood flow in specific brain areas, which can be detected with [18F]FDG PET/MRI. The SUVmean and CBFmean of the prefrontal cortex and cingulum can serve as quantitative measures for detecting executive functioning problems. Hippocampal CBFmean could also be useful for monitoring memory problems.

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.

Abstract 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. Graphical Abstract

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.