Citations

Abstract Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare central nervous system tumors. Our understanding of the clinical course, prognostic factors, and optimal treatment strategies remains limited. Histologic, molecular, and clinical data were collected and analyzed for 25 patients with DLGNT reviewed at St. Jude Children’s Research Hospital. The median age at diagnosis was 6 years (11 months-20 years). Nineteen (72%) patients were male. The disease was localized at diagnosis in 12 (48.0%) patients, with most tumors localized in the spinal cord. BRAF fusion was present in 22 (95.6%) of 23 patients who had material for testing. Of 18 patients who had tissue for DNA methylation profiling, 3 (16.7%) matched to DLGNT MC-1, 3 (16.7%) to DLGNT MC-2, and 12 (66.7%) did not match to a DLGNT subclass. Median follow-up was 63 months. Twenty-four (96.0%) patients received adjuvant therapy after initial diagnosis or at progression. Thirty-five cytotoxic chemotherapy and 24 single-agent targeted therapy regimens were used in 22 and 13 patients, respectively. With targeted therapy, 3 (12%) patients had partial responses. Eleven (44.0%) received radiotherapy. Median progression-free survival (PFS) after a patient’s first chemotherapy, targeted therapy, or radiotherapy regimen was 44 months (1-77), 11 months (4-39), and 16.5 months (9-23), respectively. The 5-year PFS was 18.7%±9.2, while the 5-year overall survival (OS) was 82.4%±9.2. The 5-year OS was lower in patients older than 9 years at diagnosis (60.0%±21.9 vs 91.7%±8.0, p = 0.02). Ki67 >4% was associated with worse PFS (0%±0 vs 24.6%±11.9 at 5 years, p = 0.03). Initial disease dissemination (localized vs. disseminated) and 1q gain status do not influence PFS or OS. PFS for DLGNT remains poor across all treatment modalities, including targeted therapies, despite the high frequency of BRAF fusions. Due to its rarity, establishing optimal therapeutic strategies for DLGNT requires additional treatment and outcome data and prospective multi-institutional trials.

Importance Brain metastases are common in patients with cancer, and radiation is often used for management. Among patients with more than 4 brain metastases, the effects of stereotactic radiation targeting only individual tumors, compared with whole brain radiation with hippocampal avoidance, which radiates both tumors and normal brain, remain unknown. Objective To determine whether stereotactic radiation improves symptom severity and interference with daily functioning, compared with whole brain radiation with hippocampal avoidance. Design, Setting, and Participants Phase 3, open-label, randomized clinical trial conducted at 4 United States–based centers. Eligible patients had 5 to 20 brain metastases and no prior brain-directed radiation. Enrollment occurred between April 11, 2017, and May 17, 2024 (final follow-up, March 18, 2025). Intervention Stereotactic radiation, compared with whole brain radiation with hippocampal avoidance. Main Outcomes and Measures Mean weighted patient-reported symptom severity and interference score change over 6 months postbaseline relative to baseline using the MD Anderson Symptom Inventory–Brain Tumor instrument (scale, 0-10; score change range, −10 to 10; −10 = best). A clinically meaningful Δ was defined as 0.98. Results Of 196 randomized patients (mean age, 61 years; 129 [66%] female; 176 [90%] White; median number of brain metastases, 14 [IQR, 11-18]; 49 [25%] with prior neurosurgical resection), 83 (42%) completed the 6-month assessment. For the primary outcome, between baseline and postbaseline assessments through the 6-month follow-up, stereotactic radiation changed the weighted composite MD Anderson Symptom Inventory–Brain Tumor score from 2.69 to 2.37 (mean change, −0.32) and hippocampal-avoidance whole brain radiation changed the score from 2.29 to 3.03 (mean change, 0.74) (mean difference, −1.06 [95% CI, −1.54 to −0.58]; P < .001). Related grade 3-5 adverse events occurred in 12 patients (12%) in the stereotactic radiation group and 13 patients (13%) in the hippocampal-avoidance whole brain radiation group; grade 1-3 fatigue was most frequent (27 [28%] vs 43 [44%], respectively). Conclusions and Relevance In patients with 5 to 20 brain metastases, these findings support stereotactic radiation over hippocampal-avoidance whole brain radiation to improve symptoms and interference with daily functioning, key components of quality of life. Trial Registration ClinicalTrials.gov Identifier: NCT03075072

Abstract INTRODUCTION The locus coeruleus (LC) degenerates early in Alzheimer's disease (AD). However, the extent of rostrocaudal degeneration across clinicopathologic heterogeneity remains underexplored in AD. METHODS Using digital pathology, we quantified LC neuronal density and area at three neuroanatomic levels in a large AD series. RESULTS Analysis of neuropathologic AD subtypes revealed greater middle LC vulnerability in hippocampal sparing AD compared to typical and limbic predominant AD. Regression analyses identified distinct predictor variables associated with the degeneration of rostral and middle LC. Age at onset predicted 24% of the variability in rostral LC neuronal density, whereas Braak stage, brain weight, Lewy body disease, and age at onset accounted for 15% of the variability in middle LC. Analyses of clinical presentations revealed lower rostral LC neuronal density in non‐amnestic compared to amnestic AD cases. DISCUSSION These insights demonstrate greater LC degeneration in atypical clinicopathologic forms of AD, including hippocampal sparing, young‐onset, and non‐amnestic presentations.

ABSTRACT Skeletal muscle (SM) is an integral organ component in the pathophysiology of many acute and chronic diseases. But is there a ‘gold’ standard or accepted reference method for quantifying the amount and composition of human SM mass? Exploring that question led us to recognize the existence of a SM measurement paradigm that divides methods into two broad categories, in vitro and in vivo. In vitro methods quantify SM mass, weighing intact muscles as part of whole cadaver evaluations, only 51 of which are reported in medical literature with no recent additions. In vivo methods are used to evaluate SM in vivo, and two tiers were revealed in our analyses. An upper tier that included three methods considered ‘reference’ approaches for their accuracy and precision: computed tomography, magnetic resonance imaging and dual‐energy X‐ray absorptiometry. A lower in vivo method tier included bioimpedance analysis, three‐dimensional imaging, several approaches involving creatine metabolism, ultrasound and anthropometry. A feature common to all of the lower tier methods is their need for calibration or validation against reference approaches in the upper in vivo method tier. A critical review of the three in vivo reference methods in the upper tier revealed widely variable SM volume/mass acquisition protocols, image analysis methods and applied terminology. Some reports espouse an upper tier reference method as the ‘gold’ standard while providing minimal details of exactly how and what was measured, thus making replication in follow‐up studies difficult. Any technical issues related to an in vivo reference method are propagated to the in vivo methods in the lower tier that are calibrated or validated against them. Our review of in vivo reference methods of quantifying SM mass and composition led us to two broad recommendations. First, published reports including these reference methods should provide enough details related to acquisition and analysis protocols so that readers can replicate their findings. Second, an effort should be made to apply precise terminology in published reports in order to avoid confusion on exactly what was measured; suggestions are made on definitions of commonly used terms when referring to body composition compartments. Lastly, because there is no consensus on what constitutes a ‘gold’ standard for SM measurement, we suggest expert groups convene in the future to recommend optimum approaches and working guidelines for quantifying muscle mass and composition in vivo.

Abstract Background Brain cells secrete extracellular vesicles (EVs) containing signaling and pathological proteins related to Alzheimer's disease (AD) and related disorders. Recent studies demonstrate brain‐derived EVs (BDEVs) contain misfolded tau and are transmissible of tau pathology in the brain. However, the underlying mechanism regarding EV‐mediated tau pathology is still largely uncharacterized. Method We conducted the immuno‐affinity purification of tau in human brain‐derived EVs (BDEVs) isolated from age and sex‐matched 14 AD and 14 CTRL cases and performed tandem mass‐tag mass spectrometry to profile unbiased tau interactome in BDEVs. We used Nanotemper Monolith to validate the interaction of EV‐tau interactors with tau, and super‐resolution microscopy (Nanoimager) to detect their colocalization in a single‐EV level. We next designed siRNAs to silence EV‐tau interactors in SH‐SY5Y cells overexpressing human P301L tau (SH‐SY5Y‐P301Ltau) and assessed tau loading to EVs by Flow Nanoanalyzer. These EVs were tested for their uptake and tau seeding by human iPSC‐derived neurons (iNeurons). We finally tested the inhibitors of identified molecules on BDEV‐mediated tau propagation in vivo . Result A total of 764 proteins were identified in BDEV‐associated tau interactome from CTRL and AD patients. Sixty‐five proteins were significantly downregulated in AD BDEVs; whereas 5 proteins were significantly upregulated in AD BDEVs compared to CTRL BDEVs. The most enriched tau‐interacting proteins were significantly positively correlated with Braak stage. We confirmed the direct binding of candidate proteins to tau with micromolar binding affinities by Monolith, and their colocalization with tau in human BDEVs using Nanoimager. Silencing of candidate molecules in human SH‐SY5Y‐P301Ltau cells showed reduced loading of tau in EVs, their reduced uptake by iNeurons, and tau seeding activities. Finally, intracerebroventricular injection of neutralizing antibody against the most promising target results in reduction of tau pathology in PS19 mice expressing P301S human tau mutant. Conclusion Our study identified tau‐interacting molecules highly enriched in AD BDEVs compared to CTRL BDVs. Silencing of candidate molecule reduced tau loading to the EVs and their uptake by iNeurons and neutralizing antibody suppressed tau dissemination, highlighting them as promising therapeutic targets to halt tau pathology in AD and related tauopathy.

Abstract Background Population aging is expected to increase the burden of Alzheimer's disease (AD) and related dementias (ADRD), yet up to 45% of ADRD risk may be modified. Disparities in ADRD burden among Hispanic/Latino and Black/African Americans suggests that socioeconomic deprivation and medical comorbidities may influence AD risk. The relationship between these factors, symptomatic age of onset, and neuropathologic findings in AD remains unclear. This study aims to investigate these associations in an ethnoracially diverse, neuropathologically diagnosed AD case series. Understanding these risk factors may help develop more effective AD risk reduction strategies. Method We queried the Florida Autopsied Multi‐Ethnic (FLAME) cohort database for neuropathologically‐diagnosed AD cases with available age onset of cognitive symptoms, who self‐identified as Hispanic/Latino ( n = 75) or Black/African American ( n = 22). Cases were matched to non‐Hispanic White decedents ( n = 101) by sex and year of birth. Medical records at the time of brain donation were retrospectively reviewed, assessing completeness for demographics, clinical characteristics, and medical comorbidities (Table 1). Result The table shows a comparative analysis stratified by young‐onset AD (YOAD, onset <65 years) and late‐onset AD (LOAD, onset ≥65 years). YOAD cases had a significantly higher level of education compared to LOAD ( p = 0.003). No differences were observed in sex , APOE ε4 carriership, or Area Deprivation Index between YOAD and LOAD. However, YOAD cases had a longer disease duration and were more likely to present with atypical clinical features compared to LOAD (both p <0.001). YOAD cases also showed a faster rate of decline on MMSE compared to LOAD ( p = 0.002), higher frequency of depression ( p = 0.018), and lower frequency of stroke/TIA ( p = 0.025). YOAD cases also had lower brain weight ( p = 0.041), less cerebrovascular disease burden ( p = 0.003) and higher neurofibrillary tangle density in association cortices ( p <0.001) compared to LOAD cases. Conclusion Socioeconomic deprivation and most medical comorbidities were not associated with AD symptomatic onset. Despite having higher education levels and lower cerebrovascular burden, YOAD decedents experienced faster cognitive decline but a longer disease course, with more frequent atypical clinical presentations and depression compared to LOAD. Further discussion will address the topographic distribution of tangle and plaque pathology.

Abstract Background Extracellular vesicles (EVs) are key mediators in transferring pathological proteins associated with Alzheimer's disease (AD). The apolipoprotein E (APOE) gene, particularly the ε4 allele, is a major genetic risk factor for late‐onset AD. However, the influence of APOE genotype on the biological characteristics and cargo composition of brain‐derived extracellular vesicles (BDEVs) in AD remains poorly understood. Method In this study, BDEVs were isolated from human AD temporal cortex with APOE3/3 and APOE4/4 genotypes ( N = 20 / group). Nanoflow cytometry and super‐resolution microscopy were used to evaluate the tau load within these BDEVs. EV‐mediated tau transmission was assessed in aged human Tau KI and APP NL‐G‐F : Tau KI mice in vivo . BDEV uptake and tau seeding were evaluated in iPSC‐derived neurons through live imaging. Additionally, shotgun lipidomics and data independent acquisition proteomics were analyzed lipidome and proteome of BDEVs, respectively. Key molecules linked to APOE genotype were identified through integrated weighted gene co‐expression network and trait correlation analysis. Result APOE4/4 BDEVs exhibited a higher proportion of phosphorylated tau (pS396) at single EV levels. Upon injection of 300pg tau of BDEVs into aged Tau KI and APP NL‐G‐F : Tau KI mice, APOE4/4 BDEVs significantly increased AT8 + phosphorylated tau levels, and induced neuroinflammation in vivo . Moreover, APOE4/4 BDEVs demonstrated stronger neuronal uptake and tau transfer compared to APOE3/3 BDEVs, impairing the neuronal activity of iPSC‐derived neurons. Lipidomic revealed that APOE4/4 BDEVs were significantly more enriched in pro‐inflammatory long‐chain polyunsaturated fatty acids (PUFA) compared to APOE3/3 with Braak stage association. Furthermore, gene ontology pathway analysis using differentially expressed proteins in APOE4/4 BDEVs showed increased activity in oxidative phosphorylation and sterol‐binding. Multi‐omics integrated data revealed that upregulation of PUFA was significantly associated with elevated cell adhesion molecules and ATPase transporter activity with neural cell adhesion molecule as one of key molecule. Notably, neutralizing antibody against the molecule effectively reduced APOE4/4 BDEV internalization and mitigated EV‐mediated tau pathology in recipient cells. Conclusion Our comprehensive analysis suggested that AD APOE4/4 BDEV may enhance transmissibility of tau pathology and neuroinflammation via enriched pro‐inflammatory PUFA and cell adhesion molecules. Targeting these pathways presents a promising therapeutic strategy to mitigate disease progression, particularly in APOE4 individuals.

ABSTRACT Background Isolated chromosome 5/5q losses (–5/5q) without TP53 mutations are associated with favorable outcomes in myeloid neoplasms (MN) with <5% blasts. However, the clinical implication of concurrent −5/5q and TP53 aberrations in MN with ≥5% blasts is poorly understood. Methods Patients with TP53 ‐mutated MN carrying ≥5% blasts assessing the prognostic impact of ‐5/5q on 24‐month overall survival (OS24) were examined. Results Of 587 patients, 515 (88%) exhibited −5/5q overwhelmingly in the context of a complex karyotype (98.3% vs. 61.1% complex karyotype without −5/5q; p < .0001) and multihit TP53 allelic state (88.3% vs. 56.9%; p < .0001). Proportions of patients with blasts ≥20% were comparable between groups with and without −5/5q; p = 0.26. Notably, patients with −5/5q exhibited significantly fewer coalterations; p < .0001. Looking at outcomes, presence of −5/5q was associated with shorter median 24‐month overall survival (7.8 months vs. 11.2 months; p Log‐rank = .012), an effect restricted to subgroups with blasts <20% ( p = .039; N = 163), absent −7/7q ( p = .007; N = 225), or WHO5‐defined single hit allelic state ( p = 0.030; N = 91). Importantly, −5/5q retained independent adverse prognostic significance regardless of TP53 allelic state in a multivariable model. Furthermore, among the subset of 75 (13%) patients undergoing allogeneic stem cell transplantation, −5/5q predicted significantly shorter median 5‐year posttransplant survival (16.2 months vs. median not reached; p Log‐rank = .009). Conclusions These findings emphasize the independent prognostic relevance of chromosome 5/5q losses underscoring the clinical relevance of cytogenetic testing for −5/5q even in this high‐risk cohort.

Abstract Background Standardizing beam modeling in the treatment planning system is challenging due to machine‐specific configuration variations. Because of the proton therapy system (PTS) complexity and continuous development, there is no vendor's representative (“golden”) beam data like in LINACs at this stage. Purpose The primary goal of this study is to create a PTS‐specific repository of source model parameters and beam commissioning data for scanning proton therapy treatment planning systems and establish a set of reference values with associated bands of variations for this data. Methods We conducted a survey of 31 PTSs at 27 proton therapy centers to gather beam commissioning source model parameters used in their treatment planning system, ensuring a diverse selection of PTSs from major vendors: Hitachi, IBA, Varian, and Mevion. For each proton therapy center, we collected (i) beam meterset calibration in protons per MU, (ii) in‐air spot size at isocenter in terms of standard deviation in x‐ (crossline, σ x ) and y‐ (inline, σ y ) directions, (iii) in‐air angular spread at isocenter in x‐direction (θ x ) and y‐direction (θ y ) and (iv) distal falloff. For each PTS, we plotted each parameter as a function of nominal energy and performed polynomial regression analysis with optimal model selection based on Akaike Information Criterion. We calculated intraclass correlation coefficients (ICC) to quantify inter‐PTS variability and generated uncertainty bands representing standard deviations across PTSs for each parameter. Additionally, we computed percentage deviations of each individual PTS from the overall multi‐vendor mean to identify systematic vendor‐specific patterns and outliers across the 31 total PTSs analyzed. Results Multi‐vendor beam parameter analysis across 31 PTSs revealed systematic vendor‐specific patterns in inter‐PTS consistency and energy dependencies. Beam meterset calibration demonstrated excellent inter‐PTS consistency across most vendors (ICC: Varian ProBeam ≈ 0, IBA Proteus ONE = 0.006, Mevion S250i with HYPERSCAN = 0.015), with IBA Proteus PLUS systems showing moderate variation (ICC = 0.156 for the dedicated nozzle, ICC = 0.248, for the universal nozzle). Spot size and angular spread variability were highly vendor‐dependent, ranging from excellent consistency in IBA Proteus ONE to substantial variation in IBA Proteus PLUS with the universal nozzle (angular spread ICC = 0.566). Distal falloff maintained excellent consistency across all vendors (ICC < 0.023), indicating reliable energy spread characteristics. Uncertainty band analysis revealed characteristic energy‐dependent patterns, with most systems showing larger uncertainties at lower energies for spot size and angular spread, while IBA Proteus PLUS with the universal nozzle exhibited the largest uncertainty bands overall. Percentage deviation analysis demonstrated vendor‐specific clustering patterns, with some systems showing systematic positive or negative deviations from the multi‐vendor mean. Conclusions The reference data provided in this work will help to cross‐check the beam model during treatment planning system commissioning. Furthermore, this information is useful for Monte Carlo applications and research, where beam characteristics are required to set up phase space parameters, thereby avoiding the need to model the entire PTS. Finally, the results of this study will have indispensable educational value by providing valuable insights into the characteristics and capabilities of different PTSs.