Citations

Abstract Background Progressive Supranuclear Palsy (PSP) is a rare and severe neurodegenerative tauopathy characterized by diverse clinical phenotypes, including Richardson's syndrome (PSP‐RS), PSP‐parkinsonism (PSP‐P), PSP‐progressive gait freezing (PSP‐PGF), and PSP‐corticobasal syndrome (PSP‐CBS). Significant geographic variation exists in prevalence, clinical presentations, and prognosis. Objectives This global review aims to systematically evaluate the epidemiological variation, clinical phenotypes, diagnostic practices, and management strategies for PSP, focusing on regional disparities and identifying influencing genetic and environmental factors. Methodology A comprehensive literature search following PRISMA guidelines was conducted, analyzing studies reporting PSP epidemiology, phenotypes, diagnostic criteria, risk factors, treatments, and prognoses. Data were categorized into epidemiology, risk factors, clinical presentations, diagnosis, treatment accessibility, and outcomes, considering geographic variation. Results Global PSP prevalence ranges between 5–6.4 per 100,000, influenced by diagnostic criteria and healthcare infrastructure. Clinical manifestations commonly include supranuclear gaze palsy, frequent falls, cognitive impairment, and motor dysfunction. Prognosis significantly varies with subtype; PSP‐RS shows rapid progression and shorter survival (5–7 years), whereas PSP‐P has a milder clinical course (8–12 years). Regional variations highlight differences in genetic predispositions, notably the MAPT H1 haplotype, environmental risk factors such as dietary neurotoxins and industrial pollutants, and accessibility to comprehensive healthcare services. Diagnostic accuracy has improved with the adoption of MDS‐PSP criteria, facilitating recognition of diverse phenotypes. Conclusions Regional disparities in PSP prevalence, phenotypic presentation, and healthcare accessibility underscore the importance of standardized diagnostic criteria, targeted genetic and environmental studies, and equitable healthcare strategies. Enhanced global collaboration is essential for improving PSP diagnosis, management, and patient outcomes worldwide.

Abstract Outcomes in classic Hodgkin lymphoma (cHL) have steadily improved; however, additional therapies are needed for patients who relapse or do not respond to novel agents. Here, we report the efficacy and safety of camidanlumab tesirine (Cami), an anti-CD25 antibody-drug conjugate, in patients with relapsed/refractory cHL after brentuximab vedotin/programmed cell death protein 1 inhibitor therapies from the phase 2 ADCT-301-201 study. Eligible patients were adults with cHL who had received ≥3 previous lines of systemic therapy (or ≥2 if ineligible for hematopoietic stem cell transplant). Patients received 45 μg/kg Cami (IV, once every 3 weeks) in cycles 1 to 2, followed by 30 μg/kg IV once every 3 weeks for ≤1 year. The primary end point was overall response rate (ORR) per 2014 Lugano classification. Secondary end points included complete response rate (CRR), progression-free survival (PFS), and overall survival (OS). In total, 117 patients were enrolled with a median age of 37.0 years (range, 19-87). The ORR was 70.1% (95% confidence interval [CI], 60.9-78.2), with a CRR of 33.3% (95% CI, 24.9-42.6). The median PFS was 9.13 months (95% CI, 5.3-15.0); median OS was not reached. Thirty-three (28.2%) patients discontinued treatment because of treatment-emergent adverse events; the most common reasons were skin and subcutaneous tissue disorders (n = 10 [8.5%] patients), infections and infestations (n = 5 [4.3%]), and nervous systems disorders (n = 5 [4.3%]). Guillain-Barré–type or polyradiculopathy-type events occurred in 8 (6.8%) patients. Cami was efficacious in this heavily pretreated population; however, the efficacy was overshadowed by substantial issues with the safety profile. This trial was registered at www.clinicaltrials.gov as #NCT04052997.

Abstract Sex differences in cancer outcome, including that of glioblastoma (GBM), are shaped by biological, hormonal, and immunological factors and impact disease progression, treatment responses, survival, and tumor microenvironment (TME) interactions. Platelets regulate the immune responses and tumor progression in many cancers, but it is not clear how they contribute to these sex-based differences by affecting the dynamics of the TME. Here, we show that GBM patients exhibit heightened platelet reactivity driven by PAR4 signaling. In murine GBM models, both pharmacological inhibition of PAR4 using BMS986120 and genetic deletion of PAR4 significantly prolong survival in females but not males. This survival advantage is estrogen dependent: it is preserved in chromosomal male-hormonal female mice within the four-core genotype model and is rescued in ovariectomized mice treated with estrogen. The survival benefit is TME specific and is mediated by platelet-driven enhancement of CD8⁺ T cell infiltration into the tumor. Inhibition of platelet PAR4 signaling increases calcium signaling through an estrogen-dependent interaction between PAR4 and estrogen receptor β (ERβ)—a receptor interaction not previously described. PAR4-activated platelets within the TME suppress CD8⁺ T cell function, and depletion of CD8⁺ T cells abolishes both the tumor-induced platelet reactivity and the survival benefit conferred by PAR4 inhibition. These findings establish platelet-mediated PAR4 signaling as a critical driver of tumor progression and identify sex-specific immune responses as key to therapeutic efficacy.

Background Delirium is a state of acute brain failure causing confusion, reduced focus, and changes in alertness. It is common in older patients, occurring in 6-38% of older emergency department (ED) patients. Evidence suggests that systematic screening improves detection rates and early detection, management and reporting are critical. However, examples of operationalizing this in clinical non-research care are scarce. Objective To describe and disseminate examples of best practices for delirium screening, management, and monitoring within the ED. Methods A group of emergency physicians interested in geriatric emergency medicine (GEM) and evidence-based medicine gathered monthly to discuss ways of implementing delirium care. Members were asked to submit any electronic health record (EHR)-based interventions for delirium in current use at their institutions. One group member categorized the EHR tools by their use for screening, prevention, management, and monitoring of delirium. As a group, categorizations were reviewed and agreed upon and similarities, differences and themes were identified. Results Current EHR interventions from 5 EDs were included. We found that: 1) Screening for delirium in EDs is challenging due to the nature of the environment and the variety of tools available. 2) Prevention tools included order sets. 3) Management was accomplished with best practice alerts and order sets to help screen, prevent, address underlying causes, and manage agitation. Delirium prevention order sets emphasize optimizing patient mobility, comfort, and communication. Assessment order sets include routine labs and consultations, while management order sets for agitation provide safe medication options considering older adults’ unique physiology. 4) Utilizing dashboards for compliance monitoring offers real-time feedback, and provides an overview of adherence to clinical guidelines, regulatory standards, and patient safety protocols. Conclusion These real-world examples can be used in EDs implementing delirium programs. Further studies on how EHR interventions impact screening, diagnosis, and treatment of delirium in the ED are needed.

Abstract Objectives Large language models (LLMs) offer potential in natural language processing tasks in healthcare. Due to the need for high accuracy, understanding their limitations is essential. The purpose of this study was to evaluate the performance of LLMs in classifying radiology reports for the presence of pulmonary embolism (PE) under various conditions, including different prompt designs and data perturbations. Materials and Methods In this retrospective, institutional review board approved study, we evaluated 3 Google’s LLMs including Gemini-1.5-Pro, Gemini-1.5-Flash-001, and Gemini-1.5-Flash-002, in classifying 11 999 pulmonary CT angiography radiology reports for PE. Ground truth labels were determined by concordance between a computer vision-based PE detection (CVPED) algorithm and multiple LLM runs under various configurations. Discrepancies between algorithms’ classifications were aggregated and manually reviewed. We evaluated the effects of prompt design, data perturbations, and repeated analyses across geographic cloud regions. Performance metrics were calculated. Results Of 11 999 reports, 1296 (10.8%) were PE-positive. Accuracy across LLMs ranged between 0.953 and 0.996. The highest recall rate for a prompt modified after a review of the misclassified cases (up to 0.997). Few-shot prompting improved recall (up to 0.99), while chain-of-thought generally degraded performance. Gemini-1.5-Flash-002 demonstrated the highest robustness against data perturbations. Geographic cloud region variability was minimal for Gemini-1.5+-Pro, while the Flash models showed stable performance. Discussion and Conclusion LLMs demonstrated high performance in classifying radiology reports, though results varied with prompt design and data quality. These findings underscore the need for systematic evaluation and validation of LLMs for clinical applications, particularly in high-stakes scenarios.

ABSTRACT Transformed follicular lymphoma (tFL) is typically associated with chemotherapy resistance and a poor prognosis. There are limited data regarding outcomes after CD19‐directed chimeric antigen receptor T‐cell (CAR T) therapy in relapsed/refractory (R/R) tFL. A total of 923 adult patients with R/R tFL who received commercial CD19 CAR T therapy between 2017 and 2023 were identified in the Center for International Blood and Marrow Transplant Research registry. Median age was 64 years (range: 30–86) and median prior lines of therapy was 4 (range: 1–18). Most patients (78%) received axicabtagene ciloleucel, with 67% of patients having resistant disease at the time of CAR T infusion. At a median follow‐up of 25 months (range: 1–72) from CAR T infusion, the 2‐year overall survival (OS) was 57% (95% CI: 53–60) and progression‐free survival (PFS) was 43% (95% CI: 40–47). The 2‐year cumulative incidences of relapse or progression (rel/prog) and non‐relapse mortality (NRM) were 47% (95% CI: 44–51) and 9% (95% CI: 7–11), respectively. The overall response rate to CAR T was 76%, with a complete response rate of 63%. Grade ≥ 3 cytokine release syndrome (CRS) was observed in 7.1% and grade ≥ 3 immune effector cell–associated neurologic syndrome (ICANS) in 21.6% of patients. Multivariable analysis suggested that resistant disease status at the time of CAR T, use of bridging therapy, and high comorbidity index ≥ 3 were associated with inferior PFS and OS. Older age ≥ 60 significantly increased the risk of NRM. Our study suggests that CD19 CAR T is effective and safe for tFL.

Abstract Brexucabtagene autoleucel (brexu-cel) is a chimeric antigen receptor T-cell therapy approved for relapsed/refractory mantle cell lymphoma (R/R MCL). Here, we report real-world effectiveness and safety outcomes of brexu-cel in a prospective study of patients with R/R MCL, including subgroups based on prior treatment with Bruton's tyrosine kinase inhibitor, bendamustine, or autologous hematopoietic cell transplant (auto-HCT) and number of prior therapy lines, using Center for International Blood and Marrow Transplant Research registry data. A total of 476 patients with R/R MCL who received brexu-cel between July 2020 and December 2022 were included in the analysis. With a median follow-up of 13.5 months, the overall response rate was 91% and complete response rate was 82%. One-year overall survival and progression-free survival rates were 76% and 63%, respectively. One-year cumulative incidence of nonrelapse mortality was 8%. Prior auto-HCT was associated with better duration of response within 6 months after infusion (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.28-0.85) but greater risk of immune effector cell–associated neurotoxicity syndrome (odds ratio [OR], 1.66; 95% CI, 1.06-2.60). Prior bendamustine was associated with increased risk of prolonged thrombocytopenia (OR, 1.90; 95% CI, 1.13-3.21). In patients with 1 to 2 prior therapy lines, relapse or progression was less frequent compared with those with ≥3 prior lines (HR, 0.64; 95% CI, 0.42-1.00). Collectively, our results suggest that real-world outcomes with brexu-cel were consistent with those of the ZUMA-2 trial, regardless of prior therapy type or number of prior therapy lines.

Background Balloon guide catheters (BGCs) are adjunctive devices that may be used during mechanical thrombectomy (MT) to induce flow arrest and improve clot retrieval and reperfusion outcomes for acute ischemic stroke. As the cost-effectiveness of BGC use remains uncertain, this study assessed short- and long-term direct healthcare costs associated with BGC use versus standard guide catheters (SGC) during MT. Methods A decision tree model estimated the short-term costs (index hospitalization), long-term costs (one year after index hospitalization), and total costs for patients undergoing MT + BGC versus MT + SGC from a healthcare system perspective in the United States (US), Canada, United Kingdom (UK), Sweden, Germany, Italy, Spain, Belgium, and The Netherlands. Average device costs were sourced from public tender prices and market research data. Weighted average healthcare costs for modified Rankin Scale scores were sourced from published literature for the respective countries. A 2024 meta-analysis supporting improved outcomes with BGC provided input parameters to model treatment effects for BGC and SGC. Deterministic one-way and probabilistic sensitivity analyses evaluated the robustness of model parameters and accounted for uncertainty. Results Across all countries, long-term and total per-patient costs were lower with MT + BGC, yielding total per-patient cost savings of $6297 (US), CAD 3006 (Canada), £1828 (UK), 28,950 kr (Sweden), €1077 (Germany), €709 (Italy), €3678 (Spain), €2259 (Belgium), and €3344 (The Netherlands). The probability of MT + BGC yielding cost savings ranged 0.356–0.911 (short term), 0.962–0.975 (long term), and 0.838–0.935 (total costs). While long-term and total costs consistently favored MT + BGC, short-term cost savings showed more variability across countries. Conclusion This study demonstrates that BGC use is associated with total one-year per-patient cost savings for inpatient and postdischarge stroke care across the US, Canada, and seven European healthcare systems. Balloon guide catheters can potentially reduce post-stroke care costs and should be considered more broadly, despite the additional cost incurred by the device.