Citations

Abstract Purpose/Objective(s) To report outcomes for disseminated Medulloblastoma (stage M1-M3) who received radiation (RT) on the Pediatric Proton/Photon Consortium Registry (PPCR). Materials/Methods 71 patients were included with either M1 (6), M2 (21), or M3 (44) Medulloblastoma on PPCR. Survival (OS, Overall; EFS, Event Free) analyses were performed using the Kaplan Meier method and log rank p-values from RT start. Median follow up was calculated using the reverse Kaplan Meier method. Results Median age at RT was 7.5 years (range 2.4-21.89) and the median follow up was 4.3 years. Histology was classic (52), diffuse anaplasia (12), focal anaplasia (5), desmoplastic nodular (1), or other (1). Treatment included surgery, chemotherapy with or without stem cell support, and RT. 54 patients had gross total resection (GTR) or near total resection (NTR); 14 had subtotal resection (STR). Pre-RT chemotherapy was given in 69 (97.1%) patients; 23 had myeloablative chemotherapy with stem cell support. The 5 and 10-year OS of the entire cohort were 73% and 65%, and 5 and 10-year EFS were 65% and 59%. Patients with progression prior to RT (10 patients) had inferior OS (5-year OS 44%) compared to patients without progression pre-RT (5-year OS 78%, p = 0.045). There was a trend for better OS (p = 0.07) and improved EFS (p = 0.043) for M2 stage. GTR/NTR did not impact OS (p = 0.75) or EFS (p = 0.97) compared to STR. Craniospinal (CSI) radiation (70 patients, 99%) doses were: £ 23.4Gy (11.4%), 23.5Gy-36Gy (11.4%), or ³ 36Gy (74.3%). Patients receiving CSI ³ 36Gy had superior OS (p = 0.043), with 5 and 10-year OS of 82% and 71% compared to 5 and 10-year OS of 52% and 52% for lower dose CSI. Conclusion Full dose CSI (36Gy) for M1-M3 medulloblastoma was associated with excellent long-term survival this series, whereas lower dose CSI and progression prior to RT had inferior outcomes.

Abstract One of the most significant unmet clinical challenges in paediatric oncology is the development of novel therapeutic strategies for recurrent medulloblastoma (R-MB). MYC-driven MBs are defined as classically cold tumours with a low incidence of infiltrating immune cells, resulting in a therapeutic challenge. The identification of cell-cell interactions between tumour and immune cells may provide insight into critical intercellular communications and manipulations occurring within the tumour immune microenvironment (TME). We hypothesised that the key cell-cell interactions in MYC-driven primary and recurrent MB may reveal dominant immune-suppressive mechanisms and uncover targetable therapeutic vulnerabilities. Paired primary-recurrent bulk RNA-sequencing data, confirmed myeloid cells as the most infiltrating immune cell type in group3-MB and group4-MB. Comprehensive spatial phenotypic and cell-cell communication analyses corroborated this discovery, validating an increased incidence of macrophages in the matched-recurrent tumours. Subsequently, we used innovative algorithms for 10X MB single-cell data to predict interactions between tumour-cell ligands and immune-cell receptors within the TME; macrophages emerged as the core immune-cells involved in interactions throughout the TMEs, with the most significant ligand-receptor interaction and inflammatory response between MIF and CD74. In-depth immunohistochemistry analyses of primary and recurrent group3 and group4 tumours, and exhaustive tissue microarrays demonstrated expression of both CD74 and MIF, with limited expression of CD74 within the brain. To investigate the therapeutic potential of CD74, we developed recurrent, immune competent MYC-driven medulloblastoma mouse models. Comprehensive deconvolution analysis confirmed the TME integrity of our models to mirror that of the human disease. Locoregional delivery and repeat dosing of a bioactive-CD74 peptide demonstrated complete tumour clearance in our immune-competent mouse models of primary and recurrent MB, demonstrating the significant therapeutic potential of targeting the CD74-MIF axis in MYC-driven primary and recurrent MB. Key cellular interactions and therapeutic vulnerabilities within the tumour microenvironment of MYC-driven medulloblastoma (MB) have been identified, highlighting the CD74-MIF axis as a target for next-generation immunotherapies.

Background: Frequent pivoting, rotation, and deep hip flexion place football players at high risk for femoroacetabular impingement (FAI), a leading cause of hip pain in this population. Previous studies have primarily focused on professional National Football League athletes undergoing mixed surgical techniques, including labral debridement. Limited data exist on outcomes in younger, amateur players treated with labral repair. Purpose: To report return to sport (RTS) rates and functional outcomes at a minimum 5-year follow-up in primarily active high school and college football players undergoing primary hip arthroscopy with labral repair for FAI. Study Design: Case series, Level of evidence, 4. Methods: All football players who underwent primary hip arthroscopy with labral repair for FAI between 2010 and 2019 were identified from an institutional database. Collected data included descriptive data, radiographic parameters, surgical details, and reoperations. At a minimum 5-year follow-up, RTS outcomes and patient-reported outcome measures (PROMs), such as the Modified Harris Hip Score (mHHS) and Hip Outcome Score (HOS), were evaluated. Results: A total of 36 hips in 27 male athletes (mean age, 18 years; body mass index, 28.1 kg/m 2 ) were included. The majority of athletes competed at the high school (70%) or collegiate level (26%). Mean preoperative radiographic measurements were as follows: lateral center-edge angle, 31.6°; Tönnis angle, 4.1°; and alpha angle, 61.4°. Femoroplasty and acetabuloplasty were performed in 100% and 86% of cases, respectively. Also, 84% of players returned to football, all at the same or higher level than before surgery. At a mean follow-up of 9.8 years, all PROMs improved significantly from baseline ( P < .002). Outcome scores at follow-up were as follows: mHHS 90.5; HOS-Activities of Daily Living, 94.5; HOS-Sports-Specific Subscale, 91.1; and visual analog scale (VAS) pain with use, 2.3/10; VAS pain at rest, 1.3/10; and surgical satisfaction, 8.5/10. No patients required revision surgery. However, 2 patients (7%) underwent reoperations—including 1 for heterotopic ossification excision and 1 for periacetabular osteotomy. Conclusion: American football players who underwent primary hip arthroscopy with labral repair for FAI achieved excellent long-term outcomes, with high RTS rates at the same or higher levels, and improvements in PROMs and patient satisfaction. Despite favorable outcomes, nonmedical factors, such as graduation, may influence RTS in competitive athletes, particularly at the high school and collegiate levels.

ABSTRACT Objective To describe the practice patterns of point‐of‐care ultrasound (POCUS) and compare its usage across subgroups (adult vs. paediatric practitioners, physicians vs. nurse practitioners [NPs], high income [HI] vs. low and middle ‐income [LMI] countries). Methods Survey distributed via the Society of Critical Care Medicine in May–June 2024. Respondents reported the percentage of eligible patients in the past year for whom POCUS was used for vascular access and diagnostic purposes. Responses (0%, < 25%, 25%–50%, 50%–75%, > 75%) were converted into binary categories (> 50% use) and compared across subgroups using logistic regression. Results The survey was completed by 503 respondents from 39 countries (6% response rate): 77.7% from HI countries, 20.9% paediatric practitioners and 18.3% Nurse Practitioner (NPs)/Physician assistants (PAs). POCUS was commonly used for vascular access, and similar usage was found among NP/PAs, physicians, and adult and paediatric practitioners. Practitioners from LMI countries were less likely to use POCUS for vascular access. Basic diagnostic applications, such as assessing pleural effusion (72.5%) and left ventricular function (69.2%), were more commonly used than advanced applications like pulmonary artery pressure measurement (22%). Physicians were more likely than NPs (for some indications), and adult practitioners were more likely than paediatric practitioners (for most indications) to use POCUS for diagnostic purposes. Practitioners in LMI countries reported higher use of diagnostic applications than practitioners in HI countries. Conclusions POCUS is widely adopted in critical care but is less accepted for diagnostic use among paediatric practitioners and NP/PAs. Diagnostic utilisation is higher in LMI countries, while procedural use is lower. Impact Statement Point‐of‐care ultrasound (POCUS) is increasingly used in intensive care units to guide diagnosis and procedures. Despite its importance, little is known about how consistently it is used by different types of clinicians around the world. This international survey of critical care practitioners from 39 countries shows that POCUS is widely used, particularly for procedures, but diagnostic use remains uneven. Paediatric clinicians and advanced practice providers report lower diagnostic use, while clinicians in low‐ and middle‐income countries report higher diagnostic adoption. These findings highlight opportunities to improve access to training and support broader, more equitable use of POCUS in critical care.

ABSTRACT Background Primary lateral sclerosis (PLS) is an ultrarare upper motor neuron syndrome with a prognosis unique from classical ALS. The study of PLS is complicated by its rarity and the difficulty distinguishing PLS from ALS. We present data from a 1‐year prospective follow‐up study on PLS and efforts to distinguish it from ALS. Methods Seventy‐six PLS participants enrolled in this prospective natural history study. EMG studies, blood neurofilament light chain levels (NfLs), and demographic characteristics were obtained at baseline. At 1‐year follow‐up, repeat EMG studies were conducted to determine which participants fulfilled criteria for ALS. Baseline characteristics were then compared to determine features that predict reclassification. Results Seventy participants completed 1‐year follow‐up. Five of the 70 were reclassified to ALS (7.1%). Those reclassified had higher trends in baseline blood NfL levels (91.4 vs. 34.0 pg/mL, p = 0.13) and shorter symptom duration (39 vs. 69 months in the PLS group, p = 0.15). Reclassification was noted in both probable and definite PLS participants. All cases with a symptomatic duration of less than 2 years retained the PLS phenotype (5 of 5). NfL levels over 90 pg/mL predicted reclassification with 94% specificity and 60% sensitivity. No other features predicted reclassification to ALS. Conclusions In our population, reclassification of PLS to ALS occurred at a low frequency at 1 year follow‐up (7.1%). Baseline NfL was the strongest predictor in differentiating UMN dominant ALS from PLS at 1‐year follow‐up. Based on our data, we propose EMG and NfL criteria for enrollment in future PLS trials.

Abstract Current assessments of brain permeability rely predominantly on drug delivery to contrast-enhancing tumor regions. However, substantial portions of central nervous system (CNS) tumors reside within non-enhancing brain (NEB), where drug concentrations frequently remain subtherapeutic. This collaborative Adult Brain Tumor Consortium and Food and Drug Administration workshop aimed to identify criteria for defining NEB permeability to accomplish 2 critical objectives: (1) allocate clinical trial resources toward agents achieving therapeutic NEB concentrations and (2) minimize systemic toxicity when CNS benefit is improbable. The workshop systematically evaluated permeability assessment modalities, including drug physicochemical properties, in vitro blood-brain barrier models, and penetration into cerebrospinal fluid and normal rodent brain. Methodological approaches to determine requisite NEB drug concentrations and approaches to measuring NEB pharmacokinetics and pharmacodynamics were examined. This culminated in developing the Non-Enhancing Brain Permeability Index (NEBPI), which assigns therapeutic agents to 3 categories: sufficiently permeable, insufficiently permeable, or impermeable. The NEBPI provides a standardized framework to assist investigators and regulatory agencies to evaluate NEB penetration before human efficacy studies are initiated for agents that require direct tumor contact. Assessing NEB drug penetration is critical to improving outcomes in CNS tumors and reducing the incidence of brain metastases in systemic malignancies.

Importance Sex differences are increasingly recognized as modifiers of Alzheimer disease and related dementias, with women exhibiting greater tau burden and faster cognitive decline than men. Even though α-synuclein copathology frequently occurs in Alzheimer disease, its contribution to sex differences in disease progression is unclear. Objective To test whether α-synuclein positivity, measured using cerebrospinal fluid seed amplification assay (SAA), is differentially associated with tau accumulation in women vs men across the Alzheimer disease continuum. Design, Setting, and Participants This cohort study used longitudinal tau positron emission tomography from the Alzheimer’s Disease Neuroimaging Initiative collected between 2015 and 2023, with a median (IQR) follow-up of 1.23 (0.00-3.84) years. Participants were stratified by cerebrospinal fluid α-synuclein seed amplification assay status and sex. Participants were cognitively unimpaired or cognitively impaired (mild cognitive impairment or dementia) at baseline. Exposure Cerebrospinal fluid α-synuclein status determined by SAA and dichotomized as SAA negative or SAA positive. Main Outcomes and Measures Tau burden was quantified as standardized uptake value ratio (SUVr) in the medial temporal composite region of interest. Linear mixed-effects models tested SAA by sex by time interactions on longitudinal tau accumulation, adjusting for baseline age, baseline cognitive status, apolipoprotein E ε4 carrier status, and site. Sample size estimates were calculated to detect 25% and 50% treatment effects with 80% power in those with cognitive impairment. Results Among 415 participants (mean [SD] age, 72.3 [7.6] years; 220 women [53%]; 69 SAA positive [17%] and 346 SAA negative [83%]), there was a significant interaction between SAA status, sex, and time on tau accumulation (β, 0.061; 95% CI, 0.030-0.093; P &amp;lt; .001). Women with positive SAA results exhibited the fastest tau accumulation compared with other groups (0.066 SUVr per year; 95% CI, 0.043 to 0.089 SUVr per year; P &amp;lt; .001). Clinical trials targeting tau pathology in cognitively impaired individuals with 18-month follow-up would require 129 SAA-positive women to detect a 25% treatment effect with 80% power, compared with 518 SAA-negative women. Conclusions and Relevance In this cohort study of participants across the Alzheimer disease continuum, α-synuclein copathology was associated with faster tau accumulation in women than men. These findings may inform sex-specific interpretation of α-synuclein biomarkers and trial design.