Low-count whole-body PET/MRI restoration: an evaluation of dose reduction spectrum and five state-of-the-art artificial intelligence models.

PURPOSE: To provide a holistic and complete comparison of the five most advanced AI models in the augmentation of low-dose 18F-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 18F-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.

Artificial intelligence enables whole-body positron emission tomography scans with minimal radiation exposure.

PURPOSE: To generate diagnostic 18F-FDG PET images of pediatric cancer patients from ultra-low-dose 18F-FDG PET input images, using a novel artificial intelligence (AI) algorithm. METHODS: We used whole-body 18F-FDG-PET/MRI scans of 33 children and young adults with lymphoma (3-30 years) to develop a convolutional neural network (CNN), which combines inputs from simulated 6.25% ultra-low-dose 18F-FDG PET scans and simultaneously acquired MRI scans to produce a standard-dose 18F-FDG PET scan. The image quality of ultra-low-dose PET scans, AI-augmented PET scans, and clinical standard PET scans was evaluated by traditional metrics in computer vision and by expert radiologists and nuclear medicine physicians, using Wilcoxon signed-rank tests and weighted kappa statistics. RESULTS: The peak signal-to-noise ratio and structural similarity index were significantly higher, and the normalized root-mean-square error was significantly lower on the AI-reconstructed PET images compared to simulated 6.25% dose images (p < 0.001). Compared to the ground-truth standard-dose PET, SUVmax values of tumors and reference tissues were significantly higher on the simulated 6.25% ultra-low-dose PET scans as a result of image noise. After the CNN augmentation, the SUVmax values were recovered to values similar to the standard-dose PET. Quantitative measures of the readers' diagnostic confidence demonstrated significantly higher agreement between standard clinical scans and AI-reconstructed PET scans (kappa = 0.942) than 6.25% dose scans (kappa = 0.650). CONCLUSIONS: Our CNN model could generate simulated clinical standard 18F-FDG PET images from ultra-low-dose inputs, while maintaining clinically relevant information in terms of diagnostic accuracy and quantitative SUV measurements.

Therapy Response Assessment of Pediatric Tumors with Whole-Body Diffusion-weighted MRI and FDG PET/MRI.

Background Whole-body diffusion-weighted (DW) MRI can help detect cancer with high sensitivity. However, the assessment of therapy response often requires information about tumor metabolism, which is measured with fluorine 18 fluorodeoxyglucose (FDG) PET. Purpose To compare tumor therapy response with whole-body DW MRI and FDG PET/MRI in children and young adults. Materials and Methods In this prospective, nonrandomized multicenter study, 56 children and young adults (31 male and 25 female participants; mean age, 15 years ± 4 [standard deviation]; age range, 6-22 years) with lymphoma or sarcoma underwent 112 simultaneous whole-body DW MRI and FDG PET/MRI between June 2015 and December 2018 before and after induction chemotherapy (ClinicalTrials.gov identifier: NCT01542879). The authors measured minimum tumor apparent diffusion coefficients (ADCs) and maximum standardized uptake value (SUV) of up to six target lesions and assessed therapy response after induction chemotherapy according to the Lugano classification or PET Response Criteria in Solid Tumors. The authors evaluated agreements between whole-body DW MRI- and FDG PET/MRI-based response classifications with Krippendorff α statistics. Differences in minimum ADC and maximum SUV between responders and nonresponders and comparison of timing for discordant and concordant response assessments after induction chemotherapy were evaluated with the Wilcoxon test. Results Good agreement existed between treatment response assessments after induction chemotherapy with whole-body DW MRI and FDG PET/MRI (α = 0.88). Clinical response prediction according to maximum SUV (area under the receiver operating characteristic curve = 100%; 95% confidence interval [CI]: 99%, 100%) and minimum ADC (area under the receiver operating characteristic curve = 98%; 95% CI: 94%, 100%) were similar (P = .37). Sensitivity and specificity were 96% (54 of 56 participants; 95% CI: 86%, 99%) and 100% (56 of 56 participants; 95% CI: 54%, 100%), respectively, for DW MRI and 100% (56 of 56 participants; 95% CI: 93%, 100%) and 100% (56 of 56 participants; 95% CI: 54%, 100%) for FDG PET/MRI. In eight of 56 patients who underwent imaging after induction chemotherapy in the early posttreatment phase, chemotherapy-induced changes in tumor metabolism preceded changes in proton diffusion (P = .002). Conclusion Whole-body diffusion-weighted MRI showed significant agreement with fluorine 18 fluorodeoxyglucose PET/MRI for treatment response assessment in children and young adults. © RSNA, 2020 Online supplemental material is available for this article.

Comparison of ferumoxytol- and gadolinium chelate-enhanced MRI for assessment of sarcomas in children and adolescents.

OBJECTIVES: We compared the value of ferumoxytol (FMX)- and gadolinium (Gd)-enhanced MRI for assessment of sarcomas in paediatric/adolescent patients and hypothesised that tumour size and morphological features can be equally well assessed with both protocols. METHODS: We conducted a retrospective study of paediatric/adolescent patients with newly diagnosed bone or soft tissue sarcomas and both pre-treatment FMX- and Gd-MRI scans, which were maximal 4 weeks apart. Both protocols included T1- and T2-weighted sequences. One reader assessed tumour volumes, signal-to-noise ratios (SNR) of the primary tumour and adjacent tissues and contrast-to-noise ratios (CNR) of FMX- and Gd-MRI scans. Additionally, four readers scored FMX- and Gd-MRI scans according to 15 diagnostic parameters, using a Likert scale. The results were pooled across readers and compared between FMX- and Gd-MRI scans. Statistical methods included multivariate analyses with different models. RESULTS: Twenty-two patients met inclusion criteria (16 males, 6 females; mean age 15.3 ± 5.0). Tumour volume was not significantly different on T1-LAVA (p = 0.721), T1-SE (p = 0.290) and T2-FSE (p = 0.609) sequences. Compared to Gd-MRI, FMX-MRI demonstrated significantly lower tumour SNR on T1-LAVA (p < 0.001), equal tumour SNR on T1-SE (p = 0.104) and T2-FSE (p = 0.305), significantly higher tumour-to-marrow CNR (p < 0.001) on T2-FSE as well as significantly higher tumour-to-liver (p = 0.021) and tumour-to-vessel (p = 0.003) CNR on T1-LAVA images. Peritumoural and marrow oedema enhanced significantly more on Gd-MRI compared to FMX-MRI (p < 0.001/p = 0.002, respectively). Tumour thrombi and neurovascular bundle involvement were assessed with a significantly higher confidence on FMX-MRI (both p < 0.001). CONCLUSIONS: FMX-MRI provides equal assessment of the extent of bone and soft tissue sarcomas compared to Gd-MRI with improved tumour delineation and improved evaluation of neurovascular involvement and tumour thrombi. Therefore, FMX-MRI is a possible alternative to Gd-MRI for tumour staging in paediatric/adolescent sarcoma patients. KEY POINTS: • Ferumoxytol can be used as an alterative to gadolinium chelates for MRI staging ofpaediatric sarcomas. • Ferumoxytol-enhanced MRI provides equal assessment of tumour size and other diagnostic parameters compared to gadolinium chelate-enhanced MRI. • Ferumoxytol-enhanced MRI provides improved delineation of sarcomas from bone marrow, liver and vessels compared to gadolinium chelate-enhanced MRI.

Outcomes for pediatric patients with osteosarcoma treated with palliative radiotherapy.

BACKGROUND: Few studies have addressed the efficacy of palliative radiotherapy (RT) for pediatric osteosarcoma (OS), a disease generally considered to be radioresistant. We describe symptom relief, local control, and toxicity associated with palliative RT among children with OS. PROCEDURE: Patients diagnosed with OS at age 18 and under and treated with RT for palliation of symptomatic metastases or local recurrence at the primary site from 1997 to 2017 were included. We retrospectively reviewed details of RT, symptom improvement, local control, survival, and toxicity. RESULTS: Thirty-two courses of palliative RT were given to 20 patients with symptomatic metastatic and/or locally recurrent primary disease. The median equivalent dose in 2 Gy fractions (EQD2) was 40.0 Gy (range, 20.0-60.4). The median number of fractions per course was 15 (range, 5-39). Symptom improvement occurred in 24 (75%) courses of RT at a median time of 15.5 days (range, 3-43). In nine courses (37.5%), symptoms recurred after a median duration of symptom relief of 140 days (range, 1-882). Higher EQD2 correlated with longer duration of response (r = 0.39, P = 0.0003). Imaging revealed local failure in 3 of 14 courses followed with surveillance imaging studies (21.4%). The median time to progression was 12.9 months (range, 4.4-21.8). The median follow-up time following the first course of palliative RT was 17.5 months (range, 1.74-102.24), and median time to overall survival was 19.4 months. Toxicity was mild, with grade 2 toxicity occurring in one course (3.1%). CONCLUSIONS: RT is an effective method of symptom palliation for patients with recurrent or metastatic OS, with higher delivered dose correlating with longer symptom relief and with little associated toxicity.

Effects of malnutrition on treatment-related morbidity and survival of children with cancer in Nicaragua.

BACKGROUND: Most children with cancer live in resource-limited countries where malnutrition is often prevalent. We identified the relationship between malnutrition and treatment-related morbidity (TRM), abandonment of therapy, and survival of children with cancer in Nicaragua to better inform targeted nutritional interventions. PROCEDURE: We conducted a retrospective review of patients aged 6 months to 18 years with newly diagnosed acute lymphoblastic leukemia, acute myeloid leukemia (AML), Wilms tumor, Hodgkin lymphoma, or Burkitt lymphoma (BL) who were treated between January 1, 2004, and December 31, 2007 at Children's Hospital Manuel de Jesus Rivera in Managua, Nicaragua. Statistical analysis examined the relations among nutritional status and cancer type, risk category, TRM, and event-free survival (EFS). RESULTS: Sixty-seven percent of patients (189/282) were malnourished at diagnosis. Malnutrition was highest among patients with Wilms tumor (85.7%), BL (75%), and AML (74.3%). A total of 92.2% of patients (225/244) experienced morbidity during the first 90 days. Malnutrition was associated with severe infection (P = 0.033). Severely malnourished patients had ≥grade 3 TRM on more days (P = 0.023) and were more likely to experience severe TRM on >50% of days (P = 0.032; OR, 3.27 [95% CI, 1.05-10.16]). Malnourished patients had inferior median EFS (2.25 vs. 5.58 years; P = 0.049), and abandoned therapy more frequently (P = 0.015). CONCLUSIONS: In Nicaragua, pediatric oncology patients with malnutrition at diagnosis experienced increased TRM, abandoned therapy more frequently, and had inferior EFS. Standardized nutritional evaluation of patients with newly diagnosed cancer and targeted provision of nutritional support are essential to decrease TRM and improve outcomes.

AI Transformers for Radiation Dose Reduction in Serial Whole-Body PET Scans.

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.

Improved Detection of Bone Metastases in Children and Young Adults with Ferumoxytol-enhanced MRI.

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 (18F) 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.

Combination of Ribociclib and Gemcitabine for the Treatment of Medulloblastoma.

Group3 (G3) medulloblastoma (MB) is one of the deadliest forms of the disease for which novel treatment is desperately needed. Here we evaluate ribociclib, a highly selective CDK4/6 inhibitor, with gemcitabine in mouse and human G3MBs. Ribociclib central nervous system (CNS) penetration was assessed by in vivo microdialysis and by IHC and gene expression studies and found to be CNS-penetrant. Tumors from mice treated with short term oral ribociclib displayed inhibited RB phosphorylation, downregulated E2F target genes, and decreased proliferation. Survival studies to determine the efficacy of ribociclib and gemcitabine combination were performed on mice intracranially implanted with luciferase-labeled mouse and human G3MBs. Treatment of mice with the combination of ribociclib and gemcitabine was well tolerated, slowed tumor progression and metastatic spread, and increased survival. Expression-based gene activity and cell state analysis investigated the effects of the combination after short- and long-term treatments. Molecular analysis of treated versus untreated tumors showed a significant decrease in the activity and expression of genes involved in cell-cycle progression and DNA damage response, and an increase in the activity and expression of genes implicated in neuronal identity and neuronal differentiation. Our findings in both mouse and human patient-derived orthotopic xenograft models suggest that ribociclib and gemcitabine combination therapy warrants further investigation as a treatment strategy for children with G3MB.

A Retrospective Comparative Analysis of Outcomes and Prognostic Factors in Adult and Pediatric Patients with Osteosarcoma.

Osteosarcoma is the most common primary bone malignancy in both children and adults. Despite introduction of intensive multimodal treatment with chemotherapy and surgery, outcomes are still poor, especially for patients with metastatic disease and adults. Hence, there is an ongoing need for better prognostic markers and outcome data to inform management decisions in both the adult and pediatric setting. Here, we retrospectively analyzed 112 patients with bone osteosarcoma treated at two large adult and pediatric tertiary academic centers between 1989 and 2019. Patients were divided into an adult (≥18 years) and pediatric (<18 years) cohort for comparison. Our aim was to evaluate predictors of outcomes in pediatric and adult patients, with a specific focus on the role of methotrexate when added to a combination of doxorubicin-cisplatin; the prognostic value of tumor necrosis after neoadjuvant chemotherapy; and outlining any differences in outcomes between adults and pediatric patients that could inform clinical management. Adult patients treated with methotrexate-doxorubicin-cisplatin and those treated with doxorubicin-cisplatin had similar 5-year PFS (26%, 95%CI: 45.5%-10% vs. 50%, 95%CI: 69.6%-26.2%, p = 0.1) and 5-year OS (63%, 95%CI: 82%-34%, vs. 78%, 95%CI: 90.6%-52.6%, p = 0.5). In the adult cohort, there was no difference between patients with ≥90% necrosis and <90% necrosis in either 5-year PFS (42%, 95%CI: 71.1%-11.3% vs. 38%, 95%CI: 57.7%-18.2%, p = 0.4) or 5-year OS (85%, 95%CI: 97.8%-33.4% vs. 56%, 95%CI: 76.8%-27.6%, p = 0.4). In the pediatric cohort, compared to patients with <90% necrosis, those with ≥90% necrosis had significantly better 5-year PFS (30%, 95%CI: 49.3%-14.1% vs. 55%, 95%CI: 73.9%-38.5%, p = 0.003) and 5-year OS (64%, 95%CI: 80.8%-41.1% vs. 78%, 95%CI: 92%-60.9%, p = 0.04). Adult and pediatric patients had similar 5-year OS (69%, 95%CI: 83.2%-49.8% vs. 73%, 95%CI: 83.2%-59.3%, p = 0.8) and 5-year PFS (37%, 95%CI: 52.4%-22.9% vs. 43%, 95%CI: 56.2%-30.4% p = 0.3) even though the proportion of patients with ≥90% necrosis after neoadjuvant chemotherapy was higher for children compared to adults (60.3% vs. 30%, OR: 3.54, 95%CI: 1.38-8.46, p = 0.006). In conclusion, in adult patients, the addition of methotrexate to doxorubicin and cisplatin did not correlate with a significant survival benefit, questioning the therapeutic value of methotrexate overall. Our study confirms the prognostic utility of percent tumor necrosis after neoadjuvant chemotherapy in pediatric patients but not in adult patients. Lastly, this is one of the few reported studies where patients with osteosarcoma younger and older than 18 years had similar PFS and OS.

Validation of Deep Learning-based Augmentation for Reduced 18F-FDG Dose for PET/MRI in Children and Young Adults with Lymphoma.

PURPOSE: To investigate if a deep learning convolutional neural network (CNN) could enable low-dose fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/MRI for correct treatment response assessment of children and young adults with lymphoma. MATERIALS AND METHODS: In this secondary analysis of prospectively collected data (ClinicalTrials.gov identifier: NCT01542879), 20 patients with lymphoma (mean age, 16.4 years ± 6.4 [standard deviation]) underwent 18F-FDG PET/MRI between July 2015 and August 2019 at baseline and after induction chemotherapy. Full-dose 18F-FDG PET data (3 MBq/kg) were simulated to lower 18F-FDG doses based on the percentage of coincidence events (representing simulated 75%, 50%, 25%, 12.5%, and 6.25% 18F-FDG dose [hereafter referred to as 75%Sim, 50%Sim, 25%Sim, 12.5%Sim, and 6.25%Sim, respectively]). A U.S. Food and Drug Administration-approved CNN was used to augment input simulated low-dose scans to full-dose scans. For each follow-up scan after induction chemotherapy, the standardized uptake value (SUV) response score was calculated as the maximum SUV (SUVmax) of the tumor normalized to the mean liver SUV; tumor response was classified as adequate or inadequate. Sensitivity and specificity in the detection of correct response status were computed using full-dose PET as the reference standard. RESULTS: With decreasing simulated radiotracer doses, tumor SUVmax increased. A dose below 75%Sim of the full dose led to erroneous upstaging of adequate responders to inadequate responders (43% [six of 14 patients] for 75%Sim; 93% [13 of 14 patients] for 50%Sim; and 100% [14 of 14 patients] below 50%Sim; P < .05 for all). CNN-enhanced low-dose PET/MRI scans at 75%Sim and 50%Sim enabled correct response assessments for all patients. Use of the CNN augmentation for assessing adequate and inadequate responses resulted in identical sensitivities (100%) and specificities (100%) between the assessment of 100% full-dose PET, augmented 75%Sim, and augmented 50%Sim images. CONCLUSION: CNN enhancement of PET/MRI scans may enable 50% 18F-FDG dose reduction with correct treatment response assessment of children and young adults with lymphoma.Keywords: Pediatrics, PET/MRI, Computer Applications Detection/Diagnosis, Lymphoma, Tumor Response, Whole-Body Imaging, Technology AssessmentClinical trial registration no: NCT01542879 Supplemental material is available for this article. © RSNA, 2021.

Small-molecule screen reveals synergy of cell cycle checkpoint kinase inhibitors with DNA-damaging chemotherapies in medulloblastoma.

Medulloblastoma (MB) consists of four core molecular subgroups with distinct clinical features and prognoses. Treatment consists of surgery, followed by radiotherapy and cytotoxic chemotherapy. Despite this intensive approach, outcome remains dismal for patients with certain subtypes of MB, namely, MYC-amplified Group 3 and TP53-mutated SHH. Using high-throughput assays, six human MB cell lines were screened against a library of 3208 unique compounds. We identified 45 effective compounds from the screen and found that cell cycle checkpoint kinase (CHK1/2) inhibition synergistically enhanced the cytotoxic activity of clinically used chemotherapeutics cyclophosphamide, cisplatin, and gemcitabine. To identify the best-in-class inhibitor, multiple CHK1/2 inhibitors were assessed in mice bearing intracranial MB. When combined with DNA-damaging chemotherapeutics, CHK1/2 inhibition reduced tumor burden and increased survival of animals with high-risk MB, across multiple different models. In total, we tested 14 different models, representing distinct MB subgroups, and data were validated in three independent laboratories. Pharmacodynamics studies confirmed central nervous system penetration. In mice, combination treatment significantly increased DNA damage and apoptosis compared to chemotherapy alone, and studies with cultured cells showed that CHK inhibition disrupted chemotherapy-induced cell cycle arrest. Our findings indicated CHK1/2 inhibition, specifically with LY2606368 (prexasertib), has strong chemosensitizing activity in MB that warrants further clinical investigation. Moreover, these data demonstrated that we developed a robust and collaborative preclinical assessment platform that can be used to identify potentially effective new therapies for clinical evaluation for pediatric MB.

A Comprehensive Circulating Tumor DNA Assay for Detection of Translocation and Copy-Number Changes in Pediatric Sarcomas.

Most circulating tumor DNA (ctDNA) assays are designed to detect recurrent mutations. Pediatric sarcomas share few recurrent mutations but rather are characterized by translocations and copy-number changes. We applied Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) for detection of translocations found in the most common pediatric sarcomas. We also applied ichorCNA to the combined off-target reads from our hybrid capture to simultaneously detect copy-number alterations (CNA). We analyzed 64 prospectively collected plasma samples from 17 patients with pediatric sarcoma. Translocations were detected in the pretreatment plasma of 13 patients and were confirmed by tumor sequencing in 12 patients. Two of these patients had evidence of complex chromosomal rearrangements in their ctDNA. We also detected copy-number changes in the pretreatment plasma of 7 patients. We found that ctDNA levels correlated with metastatic status and clinical response. Furthermore, we detected rising ctDNA levels before relapse was clinically apparent, demonstrating the high sensitivity of our assay. This assay can be utilized for simultaneous detection of translocations and CNAs in the plasma of patients with pediatric sarcoma. While we describe our experience in pediatric sarcomas, this approach can be applied to other tumors that are driven by structural variants.

Differentiation of benign and malignant lymph nodes in pediatric patients on ferumoxytol-enhanced PET/MRI.

The composition of lymph nodes in pediatric patients is different from that in adults. Most notably, normal lymph nodes in children contain less macrophages. Therefore, previously described biodistributions of iron oxide nanoparticles in benign and malignant lymph nodes of adult patients may not apply to children. The purpose of our study was to evaluate if the iron supplement ferumoxytol improves the differentiation of benign and malignant lymph nodes in pediatric cancer patients on 18F-FDG PET/MRI. Methods: We conducted a prospective clinical trial from May 2015 to December 2018 to investigate the value of ferumoxytol nanoparticles for staging of children with cancer with 18F-FDG PET/MRI. Ferumoxytol is an FDA-approved iron supplement for the treatment of anemia and has been used "off-label" as an MRI contrast agent in this study. Forty-two children (7-18 years, 29 male, 13 female) received a 18F-FDG PET/MRI at 2 (n=20) or 24 hours (h) (n=22) after intravenous injection of ferumoxytol (dose 5 mg Fe/kg). The morphology of benign and malignant lymph nodes on ferumoxytol-enhanced T2-FSE sequences at 2 and 24 h were compared using a linear regression analysis. In addition, ADCmean-values, SUV-ratio (SUVmax lesion/SUVmean liver) and R2*-relaxation rate of benign and malignant lymph nodes were compared with a Mann-Whitney-U test. The accuracy of different criteria was assessed with a receiver operating characteristics (ROC) curve. Follow-up imaging for at least 6 months served as the standard of reference. Results: We examined a total of 613 lymph nodes, of which 464 (75.7%) were benign and 149 (24.3%) were malignant. On ferumoxytol-enhanced T2-FSE images, benign lymph nodes showed a hypointense hilum and hyperintense parenchyma, while malignant lymph nodes showed no discernible hilum. This pattern was not significantly different at 2 h and 24 h postcontrast (p=0.82). Benign and malignant lymph nodes showed significantly different ferumoxytol enhancement patterns, ADCmean values of 1578 and 852 x10-6 mm2/s, mean SUV-ratios of 0.5 and 2.8, and mean R2*-relaxation rate of 127.8 and 84.4 Hertz (Hz), respectively (all p<0.001). The accuracy of ADCmean, SUV-ratio and pattern (area under the curve (AUC): 0.99; 0.98; 0.97, respectively) was not significantly different (p=0.07). Compared to these three parameters, the accuracy of R2* was significantly lower (AUC: 0.93; p=0.001). Conclusion: Lymph nodes in children show different ferumoxytol-enhancement patterns on MRI than previously reported for adult patients. We found high accuracy (>90%) of ADCmean, SUV-ratio, pattern, and R2* measurements for the characterization of benign and malignant lymph nodes in children. Ferumoxytol nanoparticle accumulation at the hilum can be used to diagnose a benign lymph node. In the future, the delivery of clinically applicable nanoparticles to the hilum of benign lymph nodes could be harnessed to deliver theranostic drugs for immune cell priming.

Ferumoxytol Does Not Impact Standardized Uptake Values on PET/MR Scans.

PURPOSE: Tumor response assessments on positron emission tomography (PET)/magnetic resonance imaging (MRI) scans require correct quantification of radiotracer uptake in tumors and normal organs. Historically, MRI scans have been enhanced with gadolinium (Gd)-based contrast agents, which are now controversial due to brain deposition. Recently, ferumoxytol nanoparticles have been identified as an alternative to Gd-based contrast agents because they provide strong tissue enhancement on MR images but are not deposited in the brain. However, it is not known if the strong T1- and T2-contrast obtained with iron oxide nanoparticles such as ferumoxytol could affect MR-based attenuation correction of PET data. The purpose of our study was to investigate if ferumoxytol administration prior to a 2-deoxy-2-[18F]fluoro-D-glucose [18F]FDG PET/MR scan would change standardized uptake values (SUV) of normal organs. PROCEDURES: Thirty pediatric patients (6-18 years) with malignant tumors underwent [18F]FDG-PET/MR scans (dose 3 MBq/kg). Fifteen patients received an intravenous ferumoxytol injection (5 mg Fe/kg) prior to the [18F]FDG-PET/MR scans (group 1). Fifteen additional age- and sex-matched patients received unenhanced [18F]FDG-PET/MR scans (group 2). For attenuation correction of PET data, we used a Dixon-based gradient echo sequence (TR 4.2 ms, TE 1.1, 2.3 ms, FA 5), which accounted for soft tissue, lung, fat, and background air. We used a mixed linear effects model to compare the tissue MRI enhancement, quantified as the signal-to-noise ratio (SNR), as well as tissue radiotracer signal, quantified as SUVmean and SUVmax, between group 1 and group 2. Alpha was assumed at 0.05. RESULTS: The MRI enhancement of the blood and solid extra-cerebral organs, quantified as SNR, was significantly higher on ferumoxytol-enhanced MRI scans compared to unenhanced scans (p < 0.001). However, SUVmean and SUVmax values, corrected based on the patients' body weight or body surface area, were not significantly different between the two groups (p > 0.05). CONCLUSION: Ferumoxytol administration prior to a [18F]FDG PET/MR scan did not change standardized uptake values (SUV) of solid extra-cerebral organs. This is important, because it allows injection of ferumoxytol contrast prior to a PET/MRI procedure and, thereby, significantly accelerates image acquisition times.

Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas.

Spitzoid melanoma is a specific morphologic variant of melanoma that most commonly affects children and adolescents, and ranges on the spectrum of malignancy from low grade to overtly malignant. These tumors are generally driven by fusions of ALK, RET, NTRK1/3, MET, ROS1 and BRAF1,2. However, in approximately 50% of cases no genetic driver has been established2. Clinical whole-genome and transcriptome sequencing (RNA-Seq) of a spitzoid tumor from an adolescent revealed a novel gene fusion of MAP3K8, encoding a serine-threonine kinase that activates MEK3,4. The patient, who had exhausted all other therapeutic options, was treated with a MEK inhibitor and underwent a transient clinical response. We subsequently analyzed spitzoid tumors from 49 patients by RNA-Seq and found in-frame fusions or C-terminal truncations of MAP3K8 in 33% of cases. The fusion transcripts and truncated genes all contained MAP3K8 exons 1-8 but lacked the autoinhibitory final exon. Data mining of RNA-Seq from the Cancer Genome Atlas (TCGA) uncovered analogous MAP3K8 rearrangements in 1.5% of adult melanomas. Thus, MAP3K8 rearrangements-uncovered by comprehensive clinical sequencing of a single case-are the most common genetic event in spitzoid melanoma, are present in adult melanomas and could be amenable to MEK inhibition.

Single-Cell Transcriptomics in Medulloblastoma Reveals Tumor-Initiating Progenitors and Oncogenic Cascades during Tumorigenesis and Relapse.

Progenitor heterogeneity and identities underlying tumor initiation and relapse in medulloblastomas remain elusive. Utilizing single-cell transcriptomic analysis, we demonstrated a developmental hierarchy of progenitor pools in Sonic Hedgehog (SHH) medulloblastomas, and identified OLIG2-expressing glial progenitors as transit-amplifying cells at the tumorigenic onset. Although OLIG2+ progenitors become quiescent stem-like cells in full-blown tumors, they are highly enriched in therapy-resistant and recurrent medulloblastomas. Depletion of mitotic Olig2+ progenitors or Olig2 ablation impeded tumor initiation. Genomic profiling revealed that OLIG2 modulates chromatin landscapes and activates oncogenic networks including HIPPO-YAP/TAZ and AURORA-A/MYCN pathways. Co-targeting these oncogenic pathways induced tumor growth arrest. Together, our results indicate that glial lineage-associated OLIG2+ progenitors are tumor-initiating cells during medulloblastoma tumorigenesis and relapse, suggesting OLIG2-driven oncogenic networks as potential therapeutic targets.