Citations

Neurostimulation is an increasingly common treatment option for medically intractable epilepsy. SANTE (Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy) and Responsive Neurostimulation (RNS) System are landmark neurostimulation trials that utilized either duty cycle or a responsive stimulation paradigm. A seizure-free outcome is rarely observed with responsive and duty cycle neurostimulation devices. Chronic subthreshold cortical stimulation (CSCS) is a promising treatment for adult drug-resistant epilepsy involving eloquent cortex and has demonstrated safety and efficacy. Herein, the authors describe the surgical technique as well as details of stimulation programming involved in CSCS placement to facilitate the adoption of this promising treatment. The video can be found here: https://stream.cadmore.media/r10.3171/2024.4.FOCVID2422

TPS2700 Background: Though immunotherapy with anti-PD-1 immune checkpoint inhibitors (ICIs) has led to improvements in clinical outcomes in patients with cancer, when used as monotherapy in the advanced setting, only 18-25% of patients respond to ICI. Notably, ICI frequently lacks anti-tumor activity in immune-cold cancers where T cell priming is missing. Recent breakthroughs in identifying personal neoantigens via a comprehensive analysis of cancer sequencing data have brought increased attention to neoantigen cancer vaccines. Personalized cancer vaccines targeting neoantigens have shown early promise. While neoantigens have recently been investigated in some cancer types, the current neoantigen prediction algorithms have often focused on the MHC class-I subtype, single nucleotide mutations (SNM), small insertions and deletions (INDEL). We recently developed an informatics workflow, REAL-neo, for the identification, quality control (QC), and prioritization of both class-I and class-II human leukocyte antigen (HLA) bound neoantigens that arise from somatic SNM, INDEL, aberrant RNA splicing, and gene fusions, generating much more potent neoantigen candidates. Furthermore, we demonstrated robust T-cell response and prolonged survival by combining ICI and cancer vaccines in preclinical models. This single-arm phase I clinical trial is in progress to assess the safety, feasibility, and immunogenicity of personalized neoantigen vaccines in combination with pembrolizumab in patients with advanced solid cancers. Methods: The vaccine consists of up to 20 peptides (15-30 mer) comprising patient-specific neoantigens identified from tumor DNA and mRNA sequencing data using REAL-neo and delivered with GM-CSF as an adjuvant. The first cohort of three patients will be treated at dose level 1 consisting of 4 or 5 peptides at 300 mcg/peptide and GM-CSF 125 mcg per injection site in each of four limbs. After Cohort 1 is deemed safe, the study will expand to cohort 2, when patients will be enrolled at the same dose level for vaccine plus Pembrolizumab 200 mg i.v. Neoantigen vaccine will be given via subcutaneous injection on days 1, 4, 8, 15, and 21 (cohorts 1 and 2) and weeks 5 and 8 (booster dose for cohort 2 only). Cohort 1 has been completed without dose-limiting toxicity (DLT). Enrollment in Cohort 2 began in January 2024. AEs are assessed according to CTCAE v5. and safety findings are reviewed by data safety medical board (DSMB). Key eligibility criteria include 1) histologically confirmed locally advanced or metastatic solid malignancies and 2) cancer progression after at least one line of the standard-of-care (SOC) systemic treatment. For cohort 2, patients must be eligible to receive pembrolizumab per SOC or the treating physician’s judgment. Clinical trial information: NCT05269381 .

Abstract INTRODUCTION Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi‐site study, using a predefined hypothesis. METHODS We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes. RESULTS CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function. DISCUSSION The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID. Highlights This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection.

7006 Background: Rituximab maintenance (RM) after first-line (1L) bendamustine and rituximab (BR) in MCL did not improve progression-free survival in the MAINTAIN trial (Rummel et al, ASCO 2016) but was associated with improved survival outcomes in a North American observational study (Martin et al, JCO 2023). We sought to examine the potential benefit of RM after BR using a large observational cohort from 26 US academic centers. Methods: Patients with MCL who received 1L BR (without stem cell transplant) outside of clinical trials were included. At the landmark of 3 months after the end of BR, patients who achieved a complete response (CR) or partial response (PR) to BR and had no evidence of progressive disease (PD) or second-line (2L) therapy were deemed eligible for RM. Event-free survival (EFS) was defined as time from landmark to progression, relapse, retreatment, or death. EFS2 was defined as time from landmark to progression, relapse, or retreatment following 2L therapy or death. RM was not considered a line of therapy for either endpoint. OS was defined as time from landmark to death. Survival analysis was done with Kaplan-Meier methods and Cox regression models adjusting for sex and simplified MIPI. Results: Among 796 patients who received 1L BR in 2007-2020, 693 achieved a CR or PR. At the 3-month post-BR landmark, 613 had no evidence of PD, among whom 318 (52%) received RM and 295 did not. The RM group was younger (median age 70 vs 72, p = 0.010) and more predominantly male (78% vs 69%, p = 0.047). There was no statistical difference in stage, simplified MIPI, histology (blastoid or pleomorphic vs classic), Ki-67, TP53 alteration, complex karyotype, year of BR start, or best response to BR between the two groups. The median follow-up after the 3-month post-BR landmark was 61.3 months (95% CI 62.6-70.4). The median number of doses of RM was 10 (IQR 5-12). RM was associated with improved EFS (median 47.1 vs 29.7 months, adjusted HR 0.59, 95% CI 0.48-0.73), EFS2 (median 89.1 vs 48.3 months, adjusted HR 0.63, 95% CI 0.50-0.81), and OS (median 136.1 vs 74.3 months, adjusted HR 0.57, 95% CI 0.44-0.75) (all p values < 0.001). In patients with CR to 1L BR (n=527), 271 (51%) received RM, for a median of 11 (IQR 6-12) doses. In this subgroup, RM was associated with improved EFS (median 60.6 vs 31.5 months, adjusted HR 0.56, 95% CI 0.44-0.71), EFS2 (median 89.1 vs 48.3 months, adjusted HR 0.62, 95% CI 0.48-0.81), and OS (median 136.1 vs 75.6 months, adjusted HR 0.59, 95% CI 0.44-0.79) (all p values < 0.001). Analysis in patients with PR to 1L BR was limited by the sample size (n=86, 47 received RM). The numeric differences in median EFS (20.8 vs 11.5, log-rank p = 0.370), EFS2 (48.9 vs 30.3, log-rank p = 0.210) and OS (87.3 vs 46.9, log-rank p = 0.067) were not statistically significant. Conclusions: In this large multicenter study, RM after 1L BR was associated with improved EFS and OS, supporting its use in routine practice for patients with newly diagnosed MCL.

Abstract Rationale Although many studies have examined gene expression in lung tissue, the gene regulatory processes underlying emphysema are still not well understood. Finding efficient nonimaging screening methods and disease-modifying therapies has been challenging, but knowledge of the transcriptomic features of emphysema may help in this effort. Objectives Our goals were to identify emphysema-associated biological pathways through transcriptomic analysis of bulk lung tissue, to determine the lung cell types in which these emphysema-associated pathways are altered, and to detect unique and overlapping transcriptomic signatures in blood and lung samples. Methods Using RNA-sequencing data from 446 samples in the Lung Tissue Research Consortium and 3,606 blood samples from the COPDGene study, we examined the transcriptomic features of chest computed tomography–quantified emphysema. We also leveraged publicly available lung single-cell RNA-sequencing data to identify cell types showing chronic obstructive pulmonary disease–associated differential expression of the emphysema pathways found in the bulk analyses. Measurements and Main Results In the bulk lung RNA-sequencing analysis, 1,087 differentially expressed genes and 34 dysregulated pathways were significantly associated with emphysema. We observed alternative splicing of several genes and increased activity in pluripotency and cell barrier function pathways. Lung tissue and blood samples shared differentially expressed genes and biological pathways. Multiple lung cell types displayed dysregulation of epithelial barrier function pathways, and distinct pathway activities were observed among various macrophage subpopulations. Conclusions This study identified emphysema-related changes in gene expression and alternative splicing, cell type–specific dysregulated pathways, and instances of shared pathway dysregulation between blood and lung.

9022 Background: High quality education is crucial for hematology/oncology (H/O) training and lifelong learning. However, H/O has historically prioritized clinical and research careers over medical education careers. Consequently, few programs support H/O educators. A CoP is a group that shares “a concern or passion for something they do and learn how to do it better as they interact regularly.” We formed the ASCO Med Ed CoP in 2021 to provide a collaborative network and professional development venue for H/O educators. Methods: Following a published framework for developing a global health professions educator community (Establish-Grow-Sustain), we (ASCO Education Scholars Program graduates) developed CoP mission and vision statements and a leadership structure (Establish), formed committees and projects (Grow), and gathered at the ASCO Annual Meeting and via virtual Town Halls (Sustain). In 2023, we collected demographics and evaluated the CoP using a logic model focused on inputs, activities, outputs, and impact. Results: As of December 2023, the CoP includes 238 members from 143 institutions (38 [27%] non-U.S.): 207 (87%) ASCO members; 127 (53%) women, 106 (45%) men, 5 (2%) no response (NR); 111 (47%) White, 88 (37%) Asian/Pacific Islander, 27 (11%) Latinx/Hispanic, 12 (5%) Black/African-American, 8 (3%) Middle Eastern, 1 (0.4%) African, 16 (7%) NR; 146 (61%) hematologist/oncologists, 68 (29%) trainees, 6 (3%) radiation oncologists, 3 (1%) surgical oncologists, and 15 (6%) other professionals. The logic model is displayed (Table). Conclusions: The CoP has had an impact on its members, ASCO, and beyond and continues to grow and sustain itself by recruiting broadly, driving projects forward, and making structural adjustments for long-term sustainability. Upcoming projects include providing more educational resources and measuring outcomes such as changes in members’ knowledge, skills, and attitudes. Membership diversity continues to be a challenge and a priority. [Table: see text]

Background: While criteria for the diagnosis of nosocomial pneumonias exist, objective definitions are a challenge and there is no gold standard for diagnosis. We analyzed the impact of the implementation of a logical, consensus-based diagnostic and treatment protocol for managing nosocomial pneumonias in the cardiovascular surgery intensive care unit (CVS-ICU). Methods: We conducted a quasi-experimental, interrupted time series analysis to evaluate the impact of a diagnostic and treatment protocol for nosocomial pneumonias in the CVS-ICU. Impacts were measured relative to patient outcomes, diagnostic processes, and antimicrobial stewardship improvement. Descriptive statistics were used to analyze results. Results: Overall, 35 pre-protocol and 39 post-protocol patients were included. Primary clinical variables suggesting pneumonia in pre- and post-protocol patients were new lung consolidation (50% vs. 71%), new leukocytosis (59% vs. 64%), and positive culture (32% vs. 55%). Appropriate diagnostic testing improved (23% vs. 54%, p = 0.008) after protocol implementation. The proportion of patients meeting the criteria for nosocomial pneumonia (77% vs. 87%) was not statistically significant, though more patients in the post-protocol group met probable diagnostic criteria (51% vs. 77%). Duration of therapy was not significantly different (6 days [IQR = 5.0, 10.0] vs. 7 days [IQR = 6.0, 9.0]). Conclusions: The implementation of a diagnostic and treatment protocol for management of nosocomial pneumonias in the CVS-ICU resulted in improved diagnostic accuracy, advanced antimicrobial and diagnostic stewardship efforts, and laboratory cost savings without an adverse impact on patient-centered outcomes.

Abstract Purpose Sepsis disproportionately affects patients in rural and socially vulnerable communities. A promising strategy to address this disparity is provider‐to‐provider emergency department (ED)‐based telehealth consultation (tele‐ED). The objective of this study was to determine if county‐level social vulnerability index (SVI) was associated with tele‐ED use for sepsis and, if so, which SVI elements were most strongly associated. Methods We used data from the TELEmedicine as a Virtual Intervention for Sepsis in Rural Emergency Department study. The primary exposures were SVI aggregate and component scores. We used multivariable generalized estimating equations to model the association between SVI and tele‐ED use. Findings Our study cohort included 1191 patients treated in 23 Midwestern rural EDs between August 2016 and June 2019, of whom 326 (27.4%) were treated with tele‐ED. Providers in counties with a high SVI were less likely to use tele‐ED (adjusted odds ratio [aOR] = 0.51, 95% confidence interval [CI] 0.31‒0.87), an effect principally attributable to the housing type and transportation component of SVI (aOR = 0.44, 95% CI 0.22–0.89). Providers who treated fewer sepsis patients (1‒10 vs. 31+ over study period) and therefore may have been less experienced in sepsis care, were more likely to activate tele‐ED (aOR = 3.91, 95% CI 2.08‒7.38). Conclusions Tele‐ED use for sepsis was lower in socially vulnerable counties and higher among providers who treated fewer sepsis patients. These findings suggest that while tele‐ED increases access to specialized care, it may not completely ameliorate sepsis disparities due to its less frequent use in socially vulnerable communities.

Background Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. Methods and Results We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF enrolled in the PARAGON‐HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial using a modified aptamer proteomic assay. Baseline circulating protein concentrations significantly associated with the primary end point and the timing and occurrence of total heart failure hospitalization and cardiovascular death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared with published analyses in 2515 patients with heart failure with reduced ejection fraction from the PARADIGM‐HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity–Mortality in Patients With Chronic Heart Failure) clinical trials. We identified 288 proteins that were robustly associated with the risk of heart failure hospitalization and cardiovascular death in patients with HFpEF. The baseline proteins most strongly related to outcomes included B2M (β‐2 microglobulin), TIMP1 (tissue inhibitor of matrix metalloproteinase 1), SERPINA4 (serpin family A member 4), and SVEP1 (sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1). Overall, the protein–outcome associations in patients with HFpEF did not markedly differ as compared with patients with heart failure with reduced ejection fraction. A proteomic risk score derived in patients with HFpEF was not superior to a previous proteomic score derived in heart failure with reduced ejection fraction nor to clinical risk factors, NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), or high‐sensitivity cardiac troponin. Conclusions Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis in the PARAGON‐HF proteomic substudy. Our results demonstrate substantial similarities among serum proteomic risk markers for heart failure hospitalization and cardiovascular death when comparing clinical trial participants with heart failure across the ejection fraction spectrum. Registration URL: https://www.clinicaltrials.gov ; Unique Identifiers: NCT01920711, NCT01035255, NCT00853658.