Citations

Abstract Purpose: Combined mTOR and MEK inhibition, critical components of the RAS effector pathway underlying the pathogenesis of neurofibromatosis type 1 (NF1)–related tumors, caused regression in a malignant peripheral nerve sheath tumor (MPNST) transgenic mouse model. The primary objective was to determine the clinical benefit rate in patients with unresectable/metastatic MPNST. Patients and Methods: The study design was a multi-institutional, open-label, Simon two-stage, phase II study of the MEK inhibitor selumetinib and mTOR inhibitor sirolimus. Patients ≥12 years with histologically confirmed MPNST received selumetinib 50 mg twice daily and sirolimus 4 mg once daily, in continuous 28-day cycles. Correlative studies evaluated patient-reported pain, immune signature in peripheral blood, and cell-free DNA (cfDNA). Results: A total of 21 heavily pretreated patients [seven females; median age, 41 years (range, 16–72); and 14 with NF1] with advanced disease enrolled at five participating sites. Clinical benefit was observed in only one of seven in stage 1 and one of 14 patients in stage 2. The median number of cycles was two (range, 1–6). Most common adverse events (AE) were grade ≤2 gastrointestinal toxicity, acneiform rash, hypertriglyceridemia, mucositis, and transaminase elevation. Unlike the preclinical model, early 18F-fluorodeoxyglucose PET scan performed during cycle 1 demonstrated partial metabolic responses in five patients (24%), but these did not correlate with objective responses after cycle 2. cfDNA was able to detect MPNST with the potential to be a biomarker of response. Conclusions: The combination was safe, with manageable and expected AEs, but did not meet study parameters for further evaluation in MPNST. Correlative studies were informative and may guide future therapeutic trials of MPNST.

Abstract Background The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution. In typical (memory‐predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicenters. However, atypical (non‐amnestic‐predominant) AD variants with heterogeneous tau patterns provide a key opportunity to assess the universality of connectivity as a scaffold for tau progression. Method We included tau‐PET data from 320 subjects with atypical AD, characterized by highly heterogeneous tau patterns ( n = 139 posterior cortical atrophy/PCA‐AD; n = 103 logopenic variant primary progressive aphasia/lvPPA‐AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS‐AD) from 14 sites, with a subset of patients ( n = 78) having longitudinal tau‐PET data. As an independent sample, we further included regional post‐mortem tau stainings from 93 atypical AD patients from two sites ( n = 19 PCA‐AD, n = 32 lvPPA‐AD, n = 23 bvAD, n = 19 CBS‐AD). Gaussian mixture modeling was used to harmonize different tau‐PET tracers by transforming tau‐PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether 1) brain regions with stronger functional connectivity showed greater covariance in cross‐sectional and longitudinal tau‐PET and post‐mortem tau pathology, and 2) functional connectivity of tau‐PET epicenters and tau‐PET accumulation epicenters was associated with cross‐sectional and longitudinal tau patterns. Result Tau‐PET epicenters—defined as the 5% brain regions with the highest tau load—aligned with clinical variants, e.g. a posterior pattern in PCA‐AD (“visual AD”) and left‐hemispheric temporal predominance in lvPPA‐AD (“language AD”) (Figure 1). More strongly functionally connected regions showed correlated concurrent tau‐PET levels, which was confirmed with post‐mortem data (Figure 2). Moreover, the connectivity profile of tau‐PET epicenters and accumulation epicenters corresponded to tau‐PET progression patterns (Figure 3). Conclusion Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicenters, across all AD clinical variants. Since tau proteinopathy is a key driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant‐specific endpoints in clinical trials.

Abstract Background People living with HIV (PLHIV) are at increased risk of atherosclerotic cardiovascular disease (ASCVD), but the immunological mechanisms driving plaque formation remain unclear. This study investigated the association between peripheral immune cell subsets and carotid atherosclerotic plaques in PLHIV without prior clinical ASCVD. Methods In this multi-center cross-sectional study, virally suppressed PLHIV receiving antiretroviral therapy were enrolled from two Dutch cohorts: a discovery cohort (n = 994) and a validation cohort (n = 200). Participants underwent carotid ultrasound imaging to assess plaques using standardized criteria. Immune profiling was performed using high-dimensional flow cytometry of 355 immune cell populations. Associations with plaque were analyzed using linear regression adjusted for relevant confounders, and key findings were validated in the second cohort. Transcriptomic profiles of main cell populations were evaluated using deconvoluted bulk RNA sequencing to identify differential expression and pathway enrichment. Results Carotid plaques were present in 584 participants (49%)—502 of 994 (51%) in the discovery and 82 of 200 (41%) in the validation cohort. Plaques were associated with higher counts of several CD8+ T cell subsets, particularly PD-1-expressing cytotoxic T cells with an interferon secretion profile (CD8TC1PD1+). Transcriptomic analysis of CD8+ T cells revealed downregulated mitochondrial function and upregulated type 1 interferon and epidermal growth factor receptor signaling, indicating a senescent phenotype. Conclusions CD8+ T cell senescence may contribute to early atherosclerotic plaque formation in PLHIV. Targeting immune senescence could offer a novel strategy for cardiovascular risk reduction in this population. Clinical Trials Registration ClinicalTrials.gov Identifier: NCT03994835

Abstract Background Liver surgery carries a high risk of complications due to the complex interplay of patient-related factors, disease characteristics, and liver function. Expertise is essential for healthcare professionals managing hepatobiliary patients. This European consensus provides evidence-based guidance on selected aspects of peri- and postoperative care. Methods A modified Delphi process was used to achieve consensus, with a 70% agreement threshold. The expert panel comprised hepatobiliary surgeons, anaesthetists, hepatologists, a specialist nurse, and a physiotherapist. A systematic literature search was conducted in PubMed/MEDLINE, Embase, Web of Science, and Cochrane databases. Six topics were addressed: thromboprophylaxis; perioperative antibiotics; prehabilitation/nutrition/mobilization; bile leak including bilioenteric anastomosis leaks; post-hepatectomy haemorrhage; and post-hepatectomy liver failure (PHLF). Evidence appraisal and statement development followed Scottish Intercollegiate Guidelines Network methodology. A patient representative reviewed the guideline. Results Searching the literature yielded 204 included publications from an initial 6514. Thirty-two statements were formulated with a median evidence level of 2. Evidence strength varied by topic with noticeably lower evidence levels in complex surgery settings and less prevalent conditions. In some topics, study heterogeneity and specific inclusion criteria resulted in conditional recommendations, despite high-level evidence. Notably, the weakest evidence was found for perioperative thromboprophylaxis and PHLF management. Strong recommendations were formulated for prehabilitation, early postoperative mobilization, and avoidance of routine drain use. Several evidence gaps warranting multicentre studies were identified. Conclusion Optimizing peri- and postoperative care after liver resection remains challenging. Standardizing key practices and addressing evidence gaps through collaborative research are vital to improve outcomes.

Importance Emergency department (ED) visits for people with dementia often involve care (including the admission or discharge decision) with lasting effects on quality of life. Home time—a claims-based measure of days alive and outside of institutional care—provides a patient-centered way to assess downstream outcomes of ED care in this population. Objective To examine variations in home time following an ED visit by patient, facility, and visit characteristics among veterans with dementia. Design, Setting, and Participants This national retrospective cohort study used US Department of Veterans Affairs (VA) health care system data sources. Participants were veterans aged 65 to 110 years with dementia with an eligible Veterans Health Administration ED visit in fiscal years 2017 (October 1, 2016, through September 30, 2017) and/or 2018 (October 1, 2017, through September 30, 2018). Data were analyzed from May 1, 2024, to May 15, 2025. Exposures Patient, ED facility, and ED visit factors. Main Outcomes and Measures Home time, operationalized for modeling as days not at home in the 180 days after the index ED visit. Associations between patient, ED facility, and ED visit characteristics and home time were assessed using a negative binomial model. Results The study included 51 707 veterans with dementia (mean [SD] age, 79.9 [8.59] years; 97.6% male; 52.2% married). The mean (SD) number of days not at home within 180 days was 21.7 (34.5). Of the total cohort, 4.5% never returned home in the 180 days after their ED visit, while 18.2% had all subsequent days at home. ED admission (vs discharge) disposition was the factor associated with the largest increase in days not at home (rate ratio [RR], 3.18; 95% CI, 3.08-3.29). Patient factors associated with more days not at home included very high frailty (RR, 1.27; 95% CI, 1.21-1.33), unhoused status (RR, 1.50; 95% CI, 1.39-1.63), unmarried status (never married: RR, 1.24 [95% CI, 1.16-1.32]; divorced, separated, or widowed: RR, 1.24 [95% CI, 1.20-1.28]), and depression (RR, 1.13; 95% CI, 1.09-1.17). Conclusions and Relevance The findings of this cohort study suggest that home time offers a patient-centered measure of post-ED outcomes for individuals with dementia. Future work should refine its application, particularly regarding the ED disposition decision, to better evaluate the long-term impact of ED care decisions.

ABSTRACT Cytotoxic T lymphocytes (CTLs) are known to eliminate target cells through perforin-mediated, contact-dependent killing - a process limited by the number of effector T cells despite its serial nature. CTLs likely also possess a mass killing mechanism that can eliminate target cells more efficiently. Using CAR-T cells against B7H3 present on B16 tumor targets, we demonstrate that activated T cells can also kill targets in a perforin-independent manner by releasing diffusible TNF and IFNγ capable of killing nearby targets in a paracrine fashion even if they bear no antigen. Against an unperturbed target, paracrine killing is inefficient but is enhanced by the deletion of TNFR1 signaling molecules such as TAK1, HOIP, or TBK1/IKKε. Notably, these molecules are inhibited naturally by pathogen-encoded antagonists. Expression of a microbial-encoded antagonist, such as the Yersinia -encoded YopJ that antagonizes TAK1 or Ebola-encoded VP35 that antagonizes TBK1/IKKε, alters the target cell response to these cytokines from non-lethal to lethal. We propose that target cells are inherently resistant to killing by TNF and IFNγ, but the presence of a microbial factor alters this sensitivity, providing for the selective elimination of the infected cell while minimizing harm to uninfected bystander cells. We propose the term ‘pathogen-restriction’ to describe this discriminatory mechanism. Potentially, any microbial-derived factor that crosstalks with the TNF and IFNγ signaling pathways can function as a pathogen-restriction element. GRAPHICAL ABSTRACT Short Summary T cells use TNF and IFNγ to kill target cells in a paracrine manner where target elimination is restricted by the presence of pathogen-derived factors.

Abstract Background Frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominant atrophy is an emerging area of interest. Recent findings by the International Working Group (IWG) have identified this subtype as having a distinct clinical profile within the FTD spectrum (Ulugut et al., 2024, A&D). However, its genetic and pathological underpinnings remain unexplored in large, multicultural cohorts. Methods Retrospective analyses encompassing clinical, genetic, pathological, and neuroimaging data from 23 IWG sites across 13 countries in Asia, Middle East, Europe, North and South America were conducted. The study included 444 patients with FTD exhibiting predominant RATL atrophy. Results Genetic screening was performed on 51% ( n = 225) of the cohort for at least the major frontotemporal lobar degeneration (FTLD) mutations including microtubule‐associated protein tau ( MAPT ), progranulin ( GRN ), and chromosome 9 open reading frame 72 ( C9orf72 ), or dementia panels encompassing extended sets of genes. Of these, 81% were sporadic, showing negative results for the screened genes and a modified Goldman Score of ≥ 3, indicating a negative family history for dementia. The MAPT mutation was the most common genetic variant, identified in 7% of the screened cases (Figure 1). Pathological confirmation was available for 63 patients. Among the sporadic cases, transactive response DNA‐binding protein 43 type C (TDP‐C) pathology was most prevalent (60%, n = 32), while tau‐MAPT pathology was most common in the genetic cases (38%, n = 16). Fifteen cases did not fit neatly into genetic or sporadic categories, displaying heterogeneous pathologies (Figure 2). At the initial visit, compared to genetic cases, patients with TDP‐C pathology were older, and more frequently exhibited semantic deficits, with less frequent attention difficulties and executive dysfunction. No differences were observed in sex distribution, symptom duration or disease severity between genetic and sporadic TDP‐C cases. However, left handedness was more common in TDP‐C cases (14%) compared to genetic cases (5%). Conclusion While FTD with RATL atrophy primarily appears sporadic, a significant proportion of cases exhibit genetic variants. These sporadic and genetic subtypes display distinct neuropathological features and clinical manifestations. Given the implications for therapeutic strategies, precise clinical and molecular subtyping is critical for enhancing patient management and ensuring appropriate enrollment in clinical trials.

Abstract Background People living with dementia (PLWD) face short‐term risks following emergency department (ED) visits. However, the long‐term impacts of ED visits on PLWD quality of life are not well characterized. Home time‐ days alive and outside hospitals or other care settings‐ is an emerging measure that can reflect longer‐term outcomes. We aimed to identify patient and ED visit characteristics associated with variation in home time after an ED visit. Method Retrospective observational study of Veteran PLWD with ≥1 VA ED visit between 10/01/2016 and 09/30/2018. We used VA and CMS data sources to define veteran characteristics and outcomes. Primary outcome was home time in the 180 days after an ED visit, defined as days alive and not in an ED, inpatient, post‐acute, or a nursing home setting. We used a negative binomial model to evaluate the associations between covariates and home time with VAMC‐level random effects to account for correlation among patients at the same VAMC. Result Our final cohort comprised 51,707 Veteran PLWD, predominantly male (97.6%) and white (73.0%), with mean age 79.9 (SD 8.59). Most lived in urban areas (74.4%), and 52.2% were married. Characteristics associated with reduced home time included older age (RR 1.06, 95% CI 1.05‐1.07), never married (RR 1.24; 1.16‐1.32) or divorced/widowed (RR 1.24; 1.20, 1.28), depression (RR 1.13; 1.09, 1.17), and ED visits for chronic conditions (RR 1.13; 1.08, 1.18). Female sex (RR 0.88; 0.79‐0.97) and lower clinical frailty (RR 0.79; 0.75, 0.83) were associated with more home time. Conclusion Patient and ED visit characteristics impact home time up to 180 days after an ED visit. Older, frailer, unmarried, male patients and those presenting with chronic conditions experienced reduced home time, suggesting directions for targeted interventions. Efforts such as enhanced discharge planning and addressing psychosocial factors (e.g., depression) could improve quality of life.

Abstract Background Tau‐PET provides critical topographic information on tau deposition in the living brain. Integrating research‐based practices into clinical settings through qualitative methods, such as visual reads, is becoming increasingly important. This study aims to compare the performance of existing visual reading methods for [ 18 F]Flortaucipir (FTP) and [ 18 F]MK‐6240 (MK) and provide preliminary data toward a unified visual reading approach for all tau‐PET tracers using a head‐to‐head dataset. Methods The study design and development plans are illustrated in Figure 1. To evaluate previously published visual reading methods, two blinded raters conducted FTP and MK visual reads on 340 participants from the HEAD study. A unified visual reading method was developed and tested on 101 participants, using a composite of adjusted Braak regions to determine 3 stages of severity while harmonizing between tracers. For external validation, the method will be tested on four additional cohorts, each using one of the following tracers: FTP, MK, PI, or RO. Results Inter‐rater agreement using previous methods (Figure 2A) showed high Cohen's kappa values (0.71‐0.77) for the low and high tau burden categories in both FTP and MK visual reads. However, agreement was substantially lower in the non‐AD‐like category , leading to overall agreement rates of 0.55 for FTP and 0.69 for MK . In contrast, the method developed here improved inter‐rater agreement across all categories (0.87‐0.96) and introduced a moderate tau (0.79‐0.83) burden group (Figure 2B), leading to higher overall agreement rates of 0.81 for FTP and 0.87 for MK (Figure 2C). For inter‐tracer agreement (Figure 3), previous methods resulted in discordant visual reads for FTP and MK in 34.4% of cases for rater 1 and 24.7% for rater 2. The developed method reduced this disagreement to 11.9% (rater 1) and 15.8% (rater 2), demonstrating improved consistency across different tracers. Conclusion This study demonstrates that previously published visual reading methods produced varying classifications depending on the tracer used. The method proposed here improved inter‐rater and inter‐tracer visual read agreements by developing a unified, tracer‐agnostic approach easy to be used. Importantly, this clinician‐friendly method has the potential for widespread adoption, offering a single harmonized visual reading technique for all tau‐PET tracers.