Citations

Abstract Introduction Postoperative radiotherapy is an adjuvant therapy for brain metastases(BrMs) that improves local recurrence(LR). The radiosensitivity index(RSI) is a 10-gene index of pan-cancer molecular radiosensitivity previously validated for predicting radiotherapy response in clinical datasets. In this external validation study, we evaluate RSI as a predictor of local recurrence(LR) after radiotherapy in resected BrM. Methods Patients from University Health Network Toronto(UHN) and McGill University who had a resected BrM and subsequently underwent whole brain radiation(WBRT) or stereotactic radiosurgery(SRS). RSI was calculated using a ranked linear regression model from the weighted expression of 10 radiosensitivity genes, with higher values corresponding to radioresistance. Radiophenotype was determined using a previously validated RSI cutoff of < 0.375 to identify radiosensitive tumors. LR was defined as recurrence in the resection cavity and overall survival(OS) was measured from time of BrM diagnosis. Results 106 BrM patients were included, comprising 29 breast, 37 GI, 33 lung, and 7 melanoma primary sources. Mean age at surgery was 59.2 years, 31.1%(n = 33) were male, 67.9%(n = 72) had WBRT, 23.6%(n = 25) had a subtotal resection, and 30.2%(n = 32) had postoperative chemotherapy. Overall, 34.0%(n = 36) patients had LR. Patients with breast BrMs had median RSI 0.70(IQR:0.55-0.75, 10.3% radiosensitive) with 48.3% LR(n = 14); gastrointestinal BrMs had median RSI 0.43(IQR: 0.35-0.46, 29.7% radiosensitive) and 24.3% LR(n = 9); lung BrMs had median RSI of 0.67(IQR:0.66-0.71, 9% radiosensitive) and 33.3% LR(n = 11); melanoma BrMs had median RSI of 0.72(IQR:0.53-0.92, 0% radiosensitive) and 28.6% LR(n = 2). After adjusting for demographics, primary organ, radiotherapy, resection extent, among others, RSI did not predict LR(p = 0.56) or OS(p = 0.61). Discussion RSI did not predict either LR or OS in patients with surgically resected BrMs status post radiotherapy, further establishing the need for improved predictive scores in this population.

Abstract INTRODUCTION Associations of arterial stiffness, measured through pulse wave velocity (PWV), with incident dementia may be driven by age‐related structural changes to the arterial wall or by elevated blood pressure. METHODS Dementia‐free White or Black participants in the community‐based Atherosclerosis Risk in Communities (ARIC) cohort study with measures of PWV were examined. The associations of carotid‐femoral PWV (cfPWV) and total, structural, and load‐dependent PWV with dementia were estimated using Poisson regression models and Cox proportional hazards models. Dementia cases were defined by physician‐adjudicated review, telephone interviews, hospitalization records, and death certificates. RESULTS Of 4818 participants included in the study population (mean age: 75 years; 41% male, 21% Black), 1067 (22%) developed dementia over a median follow‐up of 9.0 years. Higher cfPWV, total PWV, structural PWV, and load‐dependent PWV were associated with greater dementia risk. DISCUSSION Both structural and pressure‐related arterial stiffness mechanisms may underlie the link between PWV and dementia.

Abstract Background Lupus nephritis remains a major cause of chronic kidney disease and kidney failure in systemic lupus erythematosus. Glucocorticoids are central to treatment but are limited by systemic toxicity. We evaluated whether a previously characterized collagen IV α3-targeted liposomal nanoparticle formulation carrying low-dose prednisolone could attenuate established lupus nephritis in MRL/lpr mice. Methods Female MRL/lpr mice with disease present at treatment initiation and C57BL/6J control mice received saline or collagen IV α3-targeted prednisolone-loaded nanoparticles (Col4-α3-Pred-NPs). Renal outcomes were assessed by longitudinal proteinuria, glomerular filtration rate (GFR), survival, kidney histopathology, renal IgG and C3d deposition, dUTP/TUNEL-associated injury staining, and renal cytokine/chemokine profiling. Body weight, food and water intake, and blood glucose were monitored as measures of general condition and preliminary tolerability. Results Col4-α3-Pred-NPs improved survival in MRL/lpr mice, reduced cumulative proteinuria burden, and attenuated terminal GFR decline compared with saline-treated MRL/lpr controls. Treatment reduced glomerular and tubulointerstitial injury, lowered composite EGTI histopathology scores, decreased terminal kidney enlargement, reduced glomerular IgG deposition and renal dUTP-positive injury signals, and reduced renal signals for IL-28A/B, IL-7, PD-ECGF, IL-11, CCL6/C10, and IL-15. C3d deposition was not significantly altered. Nanoparticle treatment was not associated with sustained treatment-related increases in blood glucose or body-weight loss during the measured study period. Conclusions Collagen IV α3-targeted liposomal delivery of low-dose prednisolone attenuated established lupus nephritis in MRL/lpr mice and improved renal structural, functional, inflammatory, and survival outcomes. These findings support further evaluation of glomerulus-targeted nanotherapy as a potential strategy to improve the precision and therapeutic index of glucocorticoid treatment in lupus nephritis.

Abstract Standard of care RPT may result in dose-limiting side effects of the salivary glands include sialadenitis and xerostomia that are inconsistent with outcomes from external beam for equivalent ADs. This work develops a parametrizable ‘Macro-to-Micro’ (M2μ) model that demonstrates the consideration of small-scale dosimetry in comparison to conventional methods that typically assume uniform voxel or organ-level uptake. Anatomical features of the salivary gland are represented by annular structures (a centralized branching network of ducts, including excretory, lobar, interlobular) and small-scale voxels (intralobular ducts and acinar cells) with dimensions set to reproduce ex-vivo murine histopathology measurements and scaled up in size for extrapolation to humans. Simulations were performed by scoring and recording S-value histograms to the target ductal and acinar cells, for two beta emitters (177Lu, 131I) and one alpha emitter (225Ac). Four idealized activity distributions were created to assign activity to surface and volumes of the annuli, and GEANT4 v11 was used for radiation transport calculations. Comparisons against whole gland uniform spherical self-dose S-value calculations were conducted to validate the radiation transport and to highlight differences between M2μ and conventional dosimetry approaches. Analyses for both models showed greater S-value variation in comparison to the homogeneously distributed activity S-value calculation. The most notable result was that the calculated S-values differed between different branches, depending on the geometric size of the annuli. For the surrounding acinar cells, S-values from ductal cells decreased as a function of distance from the branching structures. High variability of S-values, depending on ductal cell dimensions as well as within the acinar cell distribution of the salivary gland highlights the potential clinical utility of small-scale approaches to RPT salivary gland dosimetry, contingent on clinical translation and validation. To this end, future work should further refine the model and incorporate small-scale activity distributions from pre-clinical and translational studies.

Background and Aims: Liver fibrosis and cirrhosis are major global health burdens with limited treatments. Activated HSCs drive fibrosis through increased proliferation, migration, collagen deposition and glycolysis. The aim of this study is to elucidate the signaling events that lead to enhanced glycolysis, subsequent HSC activation, and liver fibrosis. Approach and Results: Utilizing a phospho-kinase array, we identified with no lysine kinase 1 (WNK1) as a new kinase in primary human HSCs activated by the profibrotic PDGF-B. PDGF-mediated glycolysis in HSCs was attenuated by the WNK1 selective inhibitor, WNK-IN-11, as measured by live-cell metabolic assay, Glifon-300 fluorescence, Glucose-Glo assay, and glucose transporter 1 immunofluorescence. To understand how WNK1 promotes glycolysis, we employed chemical genetics where an engineered WNK1 carrying threonine 301 to glycine mutation (WNK1 T301G ) mutant with a modified ATP pocket accommodated a specific ATP-γ-S analogue to thio-phosphorylate its substrates. Thio-phosphorylated proteins were analyzed by mass spectrometry, which identified the glycolytic protein, triosephosphate isomerase 1 (TPI1), as a novel WNK1 direct substrate. TPI1 interacted with WNK1 in condensates, membrane-less phase separation structures. Condensate disruption and knockdown of TPI1 or WNK1 reduced HSC proliferation and migration in vitro. In vivo, pharmacological or genetic WNK1 inhibition significantly attenuated liver fibrosis in carbon tetrachloride and high-fat, choline-deficient, L -amino acid diet mouse models. Finally, WNK1 inhibition reduced fibrogenesis ex vivo in human precision-cut liver slices. Conclusions: These findings identify WNK1 as a previously unrecognized kinase that promotes HSC activation and liver fibrosis via TPI1-mediated glycolysis, highlighting the WNK1-TPI1 axis as a potential therapeutic target.

Importance Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by sterile ulcerative skin lesions. Multiple comorbidities and clinical features have been associated with PG, but no standardized guidelines exist for classifying PG phenotypes. Objective To develop an expert-established classification framework for PG phenotypes to inform treatment guidelines and future research endeavors. Evidence Review In this modified Delphi consensus study that included 23 board-certified dermatologists and Medical Dermatology Society members with expertise in PG, panelists completed 5 rounds of anonymous, iterative online surveys that were administered from December 2023 through July 2025. Before the beginning of the consensus exercise, a literature review was performed by nonvoting researchers to summarize existing data on PG clinical associations and comorbidities. A PubMed search from inception to September 2023 identified observational studies, narrative reviews, systematic reviews, and meta-analyses describing PG clinical associations and comorbidities that were published in English. Experts indicated their agreement with proposed PG phenotypes and disease modifiers with a consensus threshold of 70% or greater. Anonymous comments and aggregated results were presented in each subsequent round. In the final round, a framework of PG phenotypes and disease modifiers was proposed for agreement. Findings Twenty-three board-certified dermatologists and Medical Dermatology Society members with expertise in PG completed 5 rounds of iterative surveys. Consensus was reached on the final set of PG phenotypes and disease modifiers, with 83% of experts in agreement. PG phenotypes were overall classified into 2 major groups: PG with autoinflammatory syndromes and nonsyndromic PG. Nonsyndromic PG included 4 phenotypes: inflammatory bowel disease–associated PG, PG in association with hematologic cancers and blood dyscrasias, drug-induced PG, and other (including idiopathic) PG. Disease modifiers of PG phenotype presentations included involvement of special sites (head/neck, genitals, or peristomal skin) and extracutaneous manifestations. Conclusions and Relevance This expert-established, descriptive framework provides a standardized classification system for distinct PG phenotypes and its modifiers. This nomenclature may inform upcoming clinical guidelines and allow for consistency in reporting epidemiological research and outcomes among patients with PG.

BACKGROUND The authors aimed to evaluate the feasibility/safety of stereo-electroencephalography (SEEG) and SEEG-guided radiofrequency thermocoagulation (RFTC) in patients with drug-resistant epilepsy previously implanted with neuromodulation devices, using a retrospective cohort design evaluating patients treated at the Mayo Clinic Florida Epilepsy Center. OBSERVATIONS Nine patients (mean age 36.3 ± 10.9 years, 33% female) with prior implantation of neuromodulation devices were included. A vagus nerve stimulator was present in 8 of 9 patients, and 4 patients had undergone previous intracranial neuromodulation. Five patients underwent SEEG-RFTC. The mean SEEG monitoring duration was 6.5 ± 2.9 days. No intraoperative or procedural complications occurred, including hardware-related issues. No permanent or significant neurological/cognitive deficits occurred. One patient experienced transient postoperative neurological symptoms attributed to perilesional edema. Seizure reduction ranged from 50% to 75% following SEEG-RFTC. LESSONS SEEG and SEEG-RFTC are feasible in patients who have implanted neuromodulation devices, including intracranial implants. These procedures may be performed without interference with existing hardware and provide meaningful seizure reduction in highly refractory populations. Further studies with larger cohorts and longer follow-up are needed to better define efficacy and patient selection. https://thejns.org/doi/10.3171/CASE26376

Abstract Tissue-mimicking phantoms play a crucial role in evaluating new imaging modalities, simulating clinical scenarios, and ensuring the quality and reliability of imaging systems. Styrene–ethylene/butylene–styrene (SEBS) is an extremely stable and versatile material that has been recently used in ultrasound, elastography, and photoacoustic imaging across diverse applications. Despite its extensive use, a systematic viscoelastic characterization of different SEBS-based formulations reported in the literature, particularly using shear wave elastography (SWE), remains limited. To address this gap, this study investigates the viscoelastic properties of tissue-mimicking phantoms composed of SEBS, glycerol dispersions in SEBS gels, and mixtures of SEBS with low-density polyethylene (LDPE) in mineral oil, using gelatin phantoms as a reference for comparison. Viscoelastic parameters were estimated from shear wave velocity and attenuation dispersion curves using a Kelvin–Voigt model, based on SWE measurements with acoustic radiation force (ARF) excitation, shear plane-wave excitation, and complementary mechanical testing. SEBS-based phantoms exhibited broad, composition-dependent viscoelastic tunability. Increasing SEBS or LDPE content led to stiffer and more viscous responses, while glycerol primarily modulated viscosity and, at higher concentrations, also affected stiffness. Consistent and concordant values were obtained using both ARF and plane wave SWE techniques. The resulting stiffness (2–22 kPa) and viscosity (0.01–1.24 Pa⋅s) overlaps with the mechanical properties of several biological soft tissues, supporting use of these phantoms for SWE validation.

ABSTRACT Background Gastric emptying scintigraphy (GES) is considered the standard for differentiating gastroparesis from functional dyspepsia and other foregut disorders characterized by nausea and vomiting but provides only a brief physiologic snapshot that may not accurately reflect daily function. We utilized a non‐invasive wireless patch system (WPS) to characterize multiday gastric myoelectrical activity, evaluate its relationship with GES, and assess changes following a therapeutic intervention. Methods Adults referred for GES for symptoms thought to represent gastroparesis were enrolled in a prospective study. Patients wore a WPS for up to 6 days, starting on the day of scintigraphy. Gastric myoelectrical activity was analyzed and categorized into relatively weak, relatively moderate, and relatively strong activity phenotypes. A subset of patients underwent repeat monitoring following individualized therapeutic interventions (e.g., anti‐emetics, proton pump inhibitors, lifestyle changes). Results Forty‐eight patients (mean age 44; 79% female) completed the study. GES identified delayed gastric emptying in 18%, rapid in 22%, and normal in 60% of subjects. During the 4‐h concurrent GES window, gastric activity in patients with delayed emptying was lower, but this difference did not reach statistical significance ( p = 0.08). When compared to the full multiday recording period, GES results showed no correlation with the myoelectric readings. Significant day‐to‐day variability was observed, both random and systemic. In the latter category, a “Test‐Day” dip was observed with gastric activity lowest on Day 1 (GES test day) and increasing significantly on subsequent days, stabilizing by Day 4 ( p < 0.001). Healthy control subjects recorded during normal daily routines showed no such day‐to‐day variation. In the retesting cohort, anti‐emetics produced robust increases in gastric amplitude, whereas PPIs showed minimal impact. Conclusions The WPS effectively captures distinct gastric phenotypes and quantifies physiologic responses to therapy in both gastric and intestinal regions, demonstrating its clinical utility as a robust tool for evaluating and managing foregut symptoms in real‐world settings. Importantly, the multiday WPS highlights significant day‐to‐day physiologic variability in gastric activity that extends beyond the single‐day GES ‘snapshot’.