Sequential intravenous and intracerebroventricular GD2-CAR T-cell therapy for H3K27M-mutated diffuse midline gliomas.

H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the GD2 disialoganglioside and chimeric antigen receptor modified T-cells targeting GD2 (GD2-CART) eradicate DMGs in preclinical models. Arm A of the Phase I trial NCT04196413 administered one IV dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal (sDMG) diffuse midline glioma at two dose levels (DL1=1e6/kg; DL2=3e6/kg) following lymphodepleting (LD) chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) GD2-CART infusions (10-30e6 GD2-CART). Primary objectives were manufacturing feasibility, tolerability, and identification of a maximally tolerated dose of IV GD2-CART. Secondary objectives included preliminary assessments of benefit. Thirteen patients enrolled and 11 received IV GD2-CART on study [n=3 DL1(3 DIPG); n=8 DL2(6 DIPG/2 sDMG). GD2-CART manufacturing was successful for all patients. No dose-limiting toxicities (DLTs) occurred on DL1, but three patients experienced DLT on DL2 due to grade 4 cytokine release syndrome (CRS). Nine patients received ICV infusions, which were not associated with DLTs. All patients exhibited tumor inflammation-associated neurotoxicity (TIAN). Four patients demonstrated major volumetric tumor reductions (52%, 54%, 91% and 100%). One patient exhibited a complete response ongoing for >30 months since enrollment. Eight patients demonstrated neurological benefit based upon a protocol-directed Clinical Improvement Score. Sequential IV followed by ICV GD2-CART induced tumor regressions and neurological improvements in patients with DIPG and sDMG. DL1 was established as the maximally tolerated IV GD2-CART dose. Neurotoxicity was safely managed with intensive monitoring and close adherence to a management algorithm.

Children with Congenital Heart Diseases Exhibit Altered Deep Gray Matter Structures.

BACKGROUND AND OBJECTIVES: Children with congenital heart diseases (CHDs) have an increased risk of developing neurologic deficits, even in the absence of apparent brain pathology. The aim of this work was to compare quantitative macro- and microstructural properties of subcortical gray matter structures of pediatric CHD patients with normal appearing brain magnetic resonance imaging to healthy controls. METHODS: We retrospectively reviewed children with coarctation of the aorta (COA) and hypoplastic left heart syndrome (HLHS) admitted to our hospital. We identified 24 pediatric CHD patients (17 COA, 7 HLHS) with normal-appearing brain MRI. Using an atlas-based approach, the volume and apparent diffusion coefficient (ADC) were determined for the thalamus, caudate, putamen, pallidum, hippocampus, amygdala, nucleus accumbens, cerebral white matter, cerebral cortex, and brainstem. Multivariate statistics were used to compare the extracted values to reference values from 100 typically developing children without any known cardiac or neurological diseases. RESULTS: Multivariate analysis of covariance using the regional ADC and volume values as dependent variables and age and sex as co-variates revealed a significant difference between pediatric CHD patients and healthy controls (p < 0.001). Post-hoc comparisons demonstrated significantly reduced brain volumes in most subcortical brain regions investigated and elevated ADC values in the thalamus for children with CHD. No significant differences were found comparing children with COA and HLHS. CONCLUSIONS: Despite normal appearing brain MRI, children with CHD exhibit wide-spread macro-structural and regional micro-structural differences of subcortical brain structures compared to healthy controls, which could negatively impact neurodevelopment, leading to neurological deficits in childhood and beyond.

Identification of Multiclass Pediatric Low-Grade Neuroepithelial Tumor Molecular Subtype with ADC MR Imaging and Machine Learning.

BACKGROUND AND PURPOSE: Molecular biomarker identification increasingly influences the treatment planning of pediatric low-grade neuroepithelial tumors (PLGNTs). We aimed to develop and validate a radiomics-based ADC signature predictive of the molecular status of PLGNTs. MATERIALS AND METHODS: In this retrospective bi-institutional study, we searched the PACS for baseline brain MRIs from children with PLGNTs. Semiautomated tumor segmentation on ADC maps was performed using the semiautomated level tracing effect tool with 3D Slicer. Clinical variables, including age, sex, and tumor location, were collected from chart review. The molecular status of tumors was derived from biopsy. Multiclass random forests were used to predict the molecular status and fine-tuned using a grid search on the validation sets. Models were evaluated using independent and unseen test sets based on the combined data, and the area under the receiver operating characteristic curve (AUC) was calculated for the prediction of 3 classes: KIAA1549-BRAF fusion, BRAF V600E mutation, and non-BRAF cohorts. Experiments were repeated 100 times using different random data splits and model initializations to ensure reproducible results. RESULTS: Two hundred ninety-nine children from the first institution and 23 children from the second institution were included (53.6% male; mean, age 8.01 years; 51.8% supratentorial; 52.2% with KIAA1549-BRAF fusion). For the 3-class prediction using radiomics features only, the average test AUC was 0.74 (95% CI, 0.73-0.75), and using clinical features only, the average test AUC was 0.67 (95% CI, 0.66-0.68). The combination of both radiomics and clinical features improved the AUC to 0.77 (95% CI, 0.75-0.77). The diagnostic performance of the per-class test AUC was higher in identifying KIAA1549-BRAF fusion tumors among the other subgroups (AUC = 0.81 for the combined radiomics and clinical features versus 0.75 and 0.74 for BRAF V600E mutation and non-BRAF, respectively). CONCLUSIONS: ADC values of tumor segmentations have differentiative signals that can be used for training machine learning classifiers for molecular biomarker identification of PLGNTs. ADC-based pretherapeutic differentiation of the BRAF status of PLGNTs has the potential to avoid invasive tumor biopsy and enable earlier initiation of targeted therapy.

Microstructural Changes in the Brainstem Auditory Pathway in Children With Hearing Loss.

OBJECTIVE: To assess the utility of diffusion tensor imaging of the auditory pathway in children with sensorineural hearing loss (SNHL). STUDY DESIGN: Retrospective cohort study. SETTING: A single academic tertiary children's hospital. PATIENTS: Sixteen pediatric patients with bilateral SNHL of at least moderate severity in the poorer ear (eight male; mean age, 5.3 ± 4.9 yrs). Controls consisted of age- and sex-matched children with normal hearing who were imaged for nonotologic, non-neurologic medical concerns and found to have normal magnetic resonance imaging (MRI). INTERVENTIONS: Three Tesla MRI scanners were used for diffusion tensor imaging. MAIN OUTCOME MEASURES: Quantitative diffusion tensor metrics were extracted from the superior olivary nucleus (SON), inferior colliculus (IC), and ipsilateral fiber tracts between the SON and IC delineated by tractography. RESULTS: We identified differences in fractional anisotropy of the SON between the SNHL cohort and controls (0.377 ± 0.056 vs. 0.422 ± 0.052; p = 0.009), but not in the IC. There were no differences in the mean diffusivity (MD) values in the IC and SON. Among younger children (≤5 yrs), MD was decreased in the SNHL cohort compared with controls in the IC (0.918 ± 0.051 vs. 1.120 ± 0.142; p < 0.001). However, among older children (>5 yrs), there were no differences in MD (1.124 ± 0.198 vs. 0.997 ± 0.103; p = 0.119). There were no differences in MD or fractional anisotropy in the white matter fibers of the IC-SON tract. CONCLUSIONS: Our results suggest abnormal neural tracts along the central auditory pathway among children with SNHL. Longitudinal studies should assess the prognostic value of these MRI-based findings for assessing long-term outcomes and determining intervention efficacy.

iSPAN: Explainable prediction of outcomes post thrombectomy with Machine Learning.

PURPOSE: This study aimed to develop and evaluate a machine learning model and a novel clinical score for predicting outcomes in stroke patients undergoing endovascular thrombectomy. MATERIALS AND METHODS: This retrospective study included all patients aged over 18 years with an anterior circulation stroke treated at a thrombectomy centre from 2010 to 2020 with external validation. The primary outcome was day 90 mRS ≥3. Existing clinical scores (SPAN and PRE) and Machine Learning (ML) models were compared. A novel clinical score (iSPAN) was derived by adding an optimised weighting of the most important ML features to the SPAN. RESULTS: 812 patients were initially included (397 female, average age 73), 63 for external validation. The best performing clinical score and ML model were SPAN and XGB (sensitivity, specificity and accuracy 0.290, 0.967, 0.628 and 0.693, 0.783, 0.738 respectively). A significant difference was found overall and our XGB model was more accurate than SPAN (p < 0.0018). The most important features were Age, mTICI and total number of passes. The addition of 11 points for mTICI of ≤2B and 3 points for ≥3 passes to the SPAN achieved the best accuracy and was used to create the iSPAN. iSPAN was not significantly less accurate than our XGB model (p > 0.5). In the external validation set, iSPAN and SPAN achieved sensitivity, specificity, and accuracy of (0.735, 0.862, 0.79) and (0.471, 0.897, 0.67) respectively. CONCLUSION: iSPAN incorporates machine-derived features to achieve better predictions compared to existing clinical scores. It is not inferior to our XGB model and is externally generalisable.

Neuroimaging abnormalities associated with immunotherapy responsiveness in Down syndrome regression disorder.

OBJECTIVE: To determine the prevalence of neuroimaging abnormalities in individuals with Down syndrome regression disorder (DSRD) and evaluate if neuroimaging abnormalities were predictive of therapeutic responses. METHODS: A multicenter, retrospective, case-control study which reviewed neuroimaging studies of individuals with DSRD and compared them to a control cohort of individuals with Down syndrome (DS) alone was performed. Individuals aged 10-30 years and meeting international consensus criteria for DSRD were included. The presence of T1, T2/FLAIR, and SWI signal abnormalities was reviewed. Response rates to various therapies, including immunotherapy, were evaluated in the presence of neuroimaging abnormalities. RESULTS: In total, 74 individuals (35%) had either T2/FLAIR and/or SWI signal abnormality compared to 14 individuals (12%) without DSRD (p < 0.001, 95%CI: 2.18-7.63). T2/FLAIR signal abnormalities were not appreciated more frequently in individuals with DSRD (14%, 30/210) than in the control cohort (9%, 11/119) (p = 0.18, OR: 1.63, 95%CI: 0.79-3.40). SWI signal abnormalities were appreciated at a higher frequency in individuals with DSRD (24%, 51/210) compared to the control cohort (4%, 5/119) (p < 0.001, OR: 7.31, 95%CI: 2.83-18.90). T2/FLAIR signal abnormalities were localized to the frontal (40%, 12/30) and parietal lobes (37%, 11/30). SWI signal abnormalities were predominantly in the bilateral basal ganglia (94%, 49/52). Individuals with DSRD and the presence of T2/FLAIR and/or SWI signal abnormalities were much more likely to respond to immunotherapy (p < 0.001, OR: 8.42. 95%CI: 3.78-18.76) and less likely to respond to benzodiazepines (p = 0.01, OR: 0.45, 95%CI: 0.25-0.83), antipsychotics (p < 0.001, OR: 0.28, 95%CI: 0.11-0.55), or electroconvulsive therapy (p < 0.001, OR: 0.12; 95%CI: 0.02-0.78) compared to individuals without these neuroimaging abnormalities. INTERPRETATION: This study indicates that in individuals diagnosed with DSRD, T2/FLAIR, and SWI signal abnormalities are more common than previously thought and predict response to immunotherapy.

A Radiomic "Warning Sign" of Progression on Brain MRI in Individuals with MS.

BACKGROUND AND PURPOSE: MS is a chronic progressive, idiopathic, demyelinating disorder whose diagnosis is contingent on the interpretation of MR imaging. New MR imaging lesions are an early biomarker of disease progression. We aimed to evaluate a machine learning model based on radiomics features in predicting progression on MR imaging of the brain in individuals with MS. MATERIALS AND METHODS: This retrospective cohort study with external validation on open-access data obtained full ethics approval. Longitudinal MR imaging data for patients with MS were collected and processed for machine learning. Radiomics features were extracted at the future location of a new lesion in the patients' prior MR imaging ("prelesion"). Additionally, "control" samples were obtained from the normal-appearing white matter for each participant. Machine learning models for binary classification were trained and tested and then evaluated the external data of the model. RESULTS: The total number of participants was 167. Of the 147 in the training/test set, 102 were women and 45 were men. The average age was 42 (range, 21-74 years). The best-performing radiomics-based model was XGBoost, with accuracy, precision, recall, and F1-score of 0.91, 0.91, 0.91, and 0.91 on the test set, and 0.74, 0.74, 0.74, and 0.70 on the external validation set. The 5 most important radiomics features to the XGBoost model were associated with the overall heterogeneity and low gray-level emphasis of the segmented regions. Probability maps were produced to illustrate potential future clinical applications. CONCLUSIONS: Our machine learning model based on radiomics features successfully differentiated prelesions from normal-appearing white matter. This outcome suggests that radiomics features from normal-appearing white matter could serve as an imaging biomarker for progression of MS on MR imaging.

Short- and Long-Term MRI Assessed Hemodynamic Changes in Pediatric Moyamoya Patients After Revascularization.

BACKGROUND: Cerebrovascular reserve (CVR) reflects the capacity of cerebral blood flow (CBF) to change following a vasodilation challenge. Decreased CVR is associated with a higher stroke risk in patients with cerebrovascular diseases. While revascularization can improve CVR and reduce this risk in adult patients with vasculopathy such as those with Moyamoya disease, its impact on hemodynamics in pediatric patients remains to be elucidated. Arterial spin labeling (ASL) is a quantitative MRI technique that can measure CBF, CVR, and arterial transit time (ATT) non-invasively. PURPOSE: To investigate the short- and long-term changes in hemodynamics after bypass surgeries in patients with Moyamoya disease. STUDY TYPE: Longitudinal. POPULATION: Forty-six patients (11 months-18 years, 28 females) with Moyamoya disease. FIELD STRENGTH/SEQUENCE: 3-T, single- and multi-delay ASL, T1-weighted, T2-FLAIR, 3D MRA. ASSESSMENT: Imaging was performed 2 weeks before and 1 week and 6 months after surgical intervention. Acetazolamide was employed to induce vasodilation during the imaging procedure. CBF and ATT were measured by fitting the ASL data to the general kinetic model. CVR was computed as the percentage change in CBF. The mean CBF, ATT, and CVR values were measured in the regions affected by vasculopathy. STATISTICAL TESTS: Pre- and post-revascularization CVR, CBF, and ATT were compared for different regions of the brain. P-values <0.05 were considered statistically significant. RESULTS: ASL-derived CBF in flow territories affected by vasculopathy significantly increased after bypass by 41 ± 31% within a week. At 6 months, CBF significantly increased by 51 ± 34%, CVR increased by 68 ± 33%, and ATT was significantly reduced by 6.6 ± 2.9%. DATA CONCLUSION: There may be short- and long-term improvement in the hemodynamic parameters of pediatric Moyamoya patients after bypass surgery. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Increased confidence of radiomics facilitating pretherapeutic differentiation of BRAF-altered pediatric low-grade glioma.

OBJECTIVES: Currently, the BRAF status of pediatric low-grade glioma (pLGG) patients is determined through a biopsy. We established a nomogram to predict BRAF status non-invasively using clinical and radiomic factors. Additionally, we assessed an advanced thresholding method to provide only high-confidence predictions for the molecular subtype. Finally, we tested whether radiomic features provide additional predictive information for this classification task, beyond that which is embedded in the location of the tumor. METHODS: Random forest (RF) models were trained on radiomic and clinical features both separately and together, to evaluate the utility of each feature set. Instead of using the traditional single threshold technique to convert the model outputs to class predictions, we implemented a double threshold mechanism that accounted for uncertainty. Additionally, a linear model was trained and depicted graphically as a nomogram. RESULTS: The combined RF (AUC: 0.925) outperformed the RFs trained on radiomic (AUC: 0.863) or clinical (AUC: 0.889) features alone. The linear model had a comparable AUC (0.916), despite its lower complexity. Traditional thresholding produced an accuracy of 84.5%, while the double threshold approach yielded 92.2% accuracy on the 80.7% of patients with the highest confidence predictions. CONCLUSION: Models that included radiomic features outperformed, underscoring their importance for the prediction of BRAF status. A linear model performed similarly to RF but with the added benefit that it can be visualized as a nomogram, improving the explainability of the model. The double threshold technique was able to identify uncertain predictions, enhancing the clinical utility of the model. CLINICAL RELEVANCE STATEMENT: Radiomic features and tumor location are both predictive of BRAF status in pLGG patients. We show that they contain complementary information and depict the optimal model as a nomogram, which can be used as a non-invasive alternative to biopsy. KEY POINTS: • Radiomic features provide additional predictive information for the determination of the molecular subtype of pediatric low-grade gliomas patients, beyond what is embedded in the location of the tumor, which has an established relationship with genetic status. • An advanced thresholding method can help to distinguish cases where machine learning models have a high chance of being (in)correct, improving the utility of these models. • A simple linear model performs similarly to a more powerful random forest model at classifying the molecular subtype of pediatric low-grade gliomas but has the added benefit that it can be converted into a nomogram, which may facilitate clinical implementation by improving the explainability of the model.

Measuring Quantitative Cerebral Blood Flow in Healthy Children: A Systematic Review of Neuroimaging Techniques.

Cerebral blood flow (CBF) is an important hemodynamic parameter to evaluate brain health. It can be obtained quantitatively using medical imaging modalities such as magnetic resonance imaging and positron emission tomography (PET). Although CBF in adults has been widely studied and linked with cerebrovascular and neurodegenerative diseases, CBF data in healthy children are sparse due to the challenges in pediatric neuroimaging. An understanding of the factors affecting pediatric CBF and its normal range is crucial to determine the optimal CBF measuring techniques in pediatric neuroradiology. This review focuses on pediatric CBF studies using neuroimaging techniques in 32 articles including 2668 normal subjects ranging from birth to 18 years old. A systematic literature search was conducted in PubMed, Embase, and Scopus and reported following the preferred reporting items for systematic reviews and meta-analyses (PRISMA). We identified factors (such as age, gender, mood, sedation, and fitness) that have significant effects on pediatric CBF quantification. We also investigated factors influencing the CBF measurements in infants. Based on this review, we recommend best practices to improve CBF measurements in pediatric neuroimaging. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2.

The RSNA Cervical Spine Fracture CT Dataset.

This dataset is composed of cervical spine CT images with annotations related to fractures; it is available at https://www.kaggle.com/competitions/rsna-2022-cervical-spine-fracture-detection/.

DEEP MOVEMENT: Deep learning of movie files for management of endovascular thrombectomy.

OBJECTIVES: Treatment and outcomes of acute stroke have been revolutionised by mechanical thrombectomy. Deep learning has shown great promise in diagnostics but applications in video and interventional radiology lag behind. We aimed to develop a model that takes as input digital subtraction angiography (DSA) videos and classifies the video according to (1) the presence of large vessel occlusion (LVO), (2) the location of the occlusion, and (3) the efficacy of reperfusion. METHODS: All patients who underwent DSA for anterior circulation acute ischaemic stroke between 2012 and 2019 were included. Consecutive normal studies were included to balance classes. An external validation (EV) dataset was collected from another institution. The trained model was also used on DSA videos post mechanical thrombectomy to assess thrombectomy efficacy. RESULTS: In total, 1024 videos comprising 287 patients were included (44 for EV). Occlusion identification was achieved with 100% sensitivity and 91.67% specificity (EV 91.30% and 81.82%). Accuracy of location classification was 71% for ICA, 84% for M1, and 78% for M2 occlusions (EV 73, 25, and 50%). For post-thrombectomy DSA (n = 194), the model identified successful reperfusion with 100%, 88%, and 35% for ICA, M1, and M2 occlusion (EV 89, 88, and 60%). The model could also perform classification of post-intervention videos as mTICI < 3 with an AUC of 0.71. CONCLUSIONS: Our model can successfully identify normal DSA studies from those with LVO and classify thrombectomy outcome and solve a clinical radiology problem with two temporal elements (dynamic video and pre and post intervention). KEY POINTS: • DEEP MOVEMENT represents a novel application of a model applied to acute stroke imaging to handle two types of temporal complexity, dynamic video and pre and post intervention. • The model takes as an input digital subtraction angiograms of the anterior cerebral circulation and classifies according to (1) the presence or absence of large vessel occlusion, (2) the location of the occlusion, and (3) the efficacy of thrombectomy. • Potential clinical utility lies in providing decision support via rapid interpretation (pre thrombectomy) and automated objective gradation of thrombectomy outcomes (post thrombectomy).

Use of Convolutional Neural Networks to Evaluate Auricular Reconstruction Outcomes for Microtia.

OBJECTIVES: The objective of this study is to determine whether machine learning may be used for objective assessment of aesthetic outcomes of auricular reconstructive surgery. METHODS: Images of normal and reconstructed auricles were obtained from internet image search engines. Convolutional neural networks were constructed to identify auricles in 2D images in an auto-segmentation task and to evaluate whether an ear was normal versus reconstructed in a binary classification task. Images were then assigned a percent score for "normal" ear appearance based on confidence of the classification. RESULTS: Images of 1115 ears (600 normal and 515 reconstructed) were obtained. The auto-segmentation task identified auricles with 95.30% accuracy compared to manually segmented auricles. The binary classification task achieved 89.22% accuracy in identifying reconstructed ears. When the confidence of the classification was used to assign percent scores to "normal" appearance, the reconstructed ears were classified to a range of 2% (least like normal ears) to 98% (most like normal ears). CONCLUSION: Image-based analysis using machine learning can offer objective assessment without the bias of the patient or the surgeon. This methodology could be adapted to be used by surgeons to assess quality of operative outcome in clinical and research settings. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:2413-2416, 2023.

Ferumoxytol-Enhanced MRI in Children and Young Adults: State of the Art.

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.

Intracranial Artery Morphology in Pediatric Moya Moya Disease and Moya Moya Syndrome.

BACKGROUND: Moya Moya disease (MMD) and Moya Moya syndrome (MMS) are cerebrovascular disorders, which affect the internal carotid arteries (ICAs). Diagnosis and surveillance of MMD/MMS in children mostly rely on qualitative evaluation of vascular imaging, especially MR angiography (MRA). OBJECTIVE: To quantitatively characterize arterial differences in pediatric patients with MMD/MMS compared with normal controls. METHODS: MRA data sets from 17 presurgery MMD/MMS (10M/7F, mean age = 10.0 years) patients were retrospectively collected and compared with MRA data sets of 98 children with normal vessel morphology (49 male patients; mean age = 10.6 years). Using a level set segmentation method with anisotropic energy weights, the cerebral arteries were automatically extracted and used to compute the radius of the ICA, middle cerebral artery (MCA), anterior cerebral artery (ACA), posterior cerebral artery (PCA), and basilar artery (BA). Moreover, the density and the average radius of all arteries in the MCA, ACA, and PCA flow territories were quantified. RESULTS: Statistical analysis revealed significant differences comparing children with MMD/MMS and those with normal vasculature ( P < .001), whereas post hoc analyses identified significantly smaller radii of the ICA, MCA-M1, MCA-M2, and ACA ( P < .001) in the MMD/MMS group. No significant differences were found for the radii of the PCA and BA or any artery density and average artery radius measurement in the flow territories ( P > .05). CONCLUSION: His study describes the results of an automatic approach for quantitative characterization of the cerebrovascular system in patients with MMD/MMS with promising preliminary results for quantitative surveillance in pediatric MMD/MMS management.

Central Nervous System Xanthoma Disseminatum: Response to 2CdA in an Adolescent.

Xanthoma disseminatum is a normolipemic non-Langerhans cell histiocytosis characterized by red-brown rubbery papules of the skin which coalesce into plaque-like lesions with symmetric involvement of face, flexor, and intertriginous areas. Less commonly, xanthoma disseminatum may affect mucosal linings, abdominal organs, and the central nervous system, leading to endocrinopathies. We report a 12-year-old adolescent with mucosal, central nervous system, and painful cutaneous lesions, further complicated by diabetes insipidus and amenorrhea. Treatment with 2-chlorodeoxyadenosine led to relief of pain and significant improvement of mucosal, central nervous system, and cutaneous lesions, with subsequent restoration of menstrual cycles.

A deep learning-based system for survival benefit prediction of tyrosine kinase inhibitors and immune checkpoint inhibitors in stage IV non-small cell lung cancer patients: A multicenter, prognostic study.

Background: For clinical decision making, it is crucial to identify patients with stage IV non-small cell lung cancer (NSCLC) who may benefit from tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). In this study, a deep learning-based system was designed and validated using pre-therapy computed tomography (CT) images to predict the survival benefits of EGFR-TKIs and ICIs in stage IV NSCLC patients. Methods: This retrospective study collected data from 570 patients with stage IV EGFR-mutant NSCLC treated with EGFR-TKIs at five institutions between 2010 and 2021 (data of 314 patients were from a previously registered study), and 129 patients with stage IV NSCLC treated with ICIs at three institutions between 2017 and 2021 to build the ICI test dataset. Five-fold cross-validation was applied to divide the EGFR-TKI-treated patients from four institutions into training and internal validation datasets randomly in a ratio of 80%:20%, and the data from another institution was used as an external test dataset. An EfficientNetV2-based survival benefit prognosis (ESBP) system was developed with pre-therapy CT images as the input and the probability score as the output to identify which patients would receive additional survival benefit longer than the median PFS. Its prognostic performance was validated on the ICI test dataset. For diagnosing which patient would receive additional survival benefit, the accuracy of ESBP was compared with the estimations of three radiologists and three oncologists with varying degrees of expertise (two, five, and ten years). Improvements in the clinicians' diagnostic accuracy with ESBP assistance were then quantified. Findings: ESBP achieved positive predictive values of 80·40%, 75·40%, and 77·43% for additional EGFR-TKI survival benefit prediction using the probability score of 0·2 as the threshold on the training, internal validation, and external test datasets, respectively. The higher ESBP score (>0·2) indicated a better prognosis for progression-free survival (hazard ratio: 0·36, 95% CI: 0·19-0·68, p<0·0001) in patients on the external test dataset. Patients with scores >0·2 in the ICI test dataset also showed better survival benefit (hazard ratio: 0·33, 95% CI: 0·18-0·55, p<0·0001). This suggests the potential of ESBP to identify the two subgroups of benefiting patients by decoding the commonalities from pre-therapy CT images (stage IV EGFR-mutant NSCLC patients receiving additional survival benefit from EGFR-TKIs and stage IV NSCLC patients receiving additional survival benefit from ICIs). ESBP assistance improved the diagnostic accuracy of the clinicians with two years of experience from 47·91% to 66·32%, and the clinicians with five years of experience from 53·12% to 61·41%. Interpretation: This study developed and externally validated a preoperative CT image-based deep learning model to predict the survival benefits of EGFR-TKI and ICI therapies in stage IV NSCLC patients, which will facilitate optimized and individualized treatment strategies. Funding: This study received funding from the National Natural Science Foundation of China (82001904, 81930053, and 62027901), and Key-Area Research and Development Program of Guangdong Province (2021B0101420005).

Early Onset Diffusion Abnormalities in Refractory Headache Disorders.

Objective: This study sought to determine if individuals with medically refractory migraine headache have volume or diffusion abnormalities on neuroimaging compared to neurotypical individuals. Background: Neuroimaging biomarkers in headache medicine continue to be limited. Early prediction of medically refractory headache and migraine disorders could result in earlier administration of high efficacy therapeutics. Methods: A single-center, retrospective, case control study was performed. All patients were evaluated clinically between 2014 and 2018. Individuals with medically refractory migraine headache (defined by ICDH-3 criteria) without any other chronic medical diseases were enrolled. Patients had to have failed more than two therapeutics and aura was not exclusionary. The initial MRI study for each patient was reviewed. Multiple brain regions were analyzed for volume and apparent diffusion coefficient values. These were compared to 81 neurotypical control patients. Results: A total of 79 patients with medically refractory migraine headache were included and compared to 74 neurotypical controls without headache disorders. Time between clinical diagnosis and neuroimaging was a median of 24 months (IQR: 12.0-37.0). Comparison of individuals with medically refractory migraine headache to controls revealed statistically significant differences in median apparent diffusion coefficient (ADC) in multiple brain subregions (p < 0.001). Post-hoc pair-wise analysis comparing individuals with medically refractory migraine headache to control patients revealed significantly decreased median ADC values for the thalamus, caudate, putamen, pallidum, amygdala, brainstem, and cerebral white matter. No volumetric differences were observed between groups. Conclusions: In individuals with medically refractory MH, ADC changes are measurable in multiple brain structures at an early age, prior to the failure of multiple pharmacologic interventions and the diagnosis of medically refractory MH. This data supports the hypothesis that structural connectivity issues may predispose some patients toward more medically refractory pain disorders such as MH.