Citations

Purpose: To understand the current state of epilepsy surgery education delivered to epilepsy fellows in the United States. Methods: An online survey focused on characteristics of epilepsy surgery education was distributed to all 93 epilepsy fellowship program directors listed on the ACGME website (accessed in May 2022). Programs were stratified per the number of fellows currently enrolled: 0 to 3 (group A) and ≥4 (group B). Results: Forty-one of 93 (44%) epilepsy fellowship programs were included in the study. The average number of resective surgeries, ablations, or corpus callosotomies per year was mostly 0 to 30 (54%) in group A and mostly >30 (80%) in group B ( P = 0.05). The average number of intracranial implantations per year was mostly 0 to 20 (58%) in group A and mostly >20 (80%) in group B ( P < 0.05). The average number of neurostimulation implantations per year was 15 (range 0–90; vagal nerve stimulation), 7 (range 0–25; responsive neurostimulation), and 4 (range 0–10; deep brain stimulation). In 78% of programs, fellows are not required to present a minimum number of epilepsy surgery cases in multidisciplinary conference before graduation. Roughly half of programs (51%) reported not using objective measures to assess fellow competency in epilepsy surgery. Conclusions: Our results suggest significant variability in epilepsy surgery volume and, consequently, fellow exposure to surgical cases and lack of standardized, objective measures in fellow teaching and assessment in the field of epilepsy surgery across programs in the United States. We advocate development of a core epilepsy surgery curriculum including minimum standards at the national level.

OBJECTIVE Tobacco smoking is among the factors known to significantly augment the risk of untreated intracranial aneurysm (IA) growth and rupture. Smoking appears to have a variable effect on different endovascular treatment modalities. The impact of smoking on the safety, efficacy, and outcomes of Woven EndoBridge (WEB) device use for wide-neck IAs has not been evaluated. This study aimed to investigate the outcomes of WEB devices by smoking status. METHODS A retrospective multicenter analysis was conducted on the data of patients from 36 sites worldwide treated with the WEB device for intracranial saccular aneurysms. Patients were stratified based on smoking status (current, former, and never smokers). The Student t-test and chi-square test were performed for continuous and categorical variables, respectively. Multivariable logistic regression was used to adjust for confounders. RESULTS Of 1376 patients with available smoking status, 504 were current smokers, 358 were former smokers, and 514 were never smokers. Upon adjusting for significant confounders, no association was found between smoking and recurrence outcomes (OR 1.39, 95% CI 0.69–2.80; p = 0.36), thromboembolic and hemorrhagic complications, and mortality among IAs treated with the WEB device. There was no statistically significant difference in outcomes between former and never smokers (OR 1.23, 95% CI 0.70–2.18; p = 0.46). The location of aneurysms differed between smoking groups, with former smokers having more anterior circulation aneurysms compared with current and never smokers (99.0% vs 96.9% vs 95.3%; p = 0.01). In terms of clinical symptoms, headache and dizziness were more common in the never smokers compared with current and former smokers (13.9% vs 8.9% vs 7.7%, p = 0.01). CONCLUSIONS This large-scale study suggests no significant correlation between smoking and the recurrence of IAs treated with the WEB device. Biological studies are warranted to better understand the biological impact of smoking on the growth and rupture of treated IAs.

Abstract Background Treatment of high risk AmpC-producing Enterobacterales bloodstream infections (BSIs) is challenging due to the posibility of development of antibiotic resistance during treatment. The aim of this study was to analyze the impact of antimicrobial stewardship activity and IDSA guidelines adequacy in patients with high risk AmpC-producing Enterobacterales BSIs. Methods Patients with Citrobacter spp, Enterobacter spp and Klebsiella aerogenes BSIs were included between June 2019-March 2024. Outcomes of death and relapse of infection at 30 days were assessed. Adequacy of definitive antimicrobial treatment according to IDSA guidelines was evaluated. The impact of antimicrobial stewardship activity in treatment adequacy and outcome was analyzed. Analysis was performed using SPSS version 25. Results 2049 BSIs were evaluated and 67 were finally included. 80% were monomicrobial. Median patient age was 74 years, 73% were male. The most frequent microorganism isolated was Enterobacter cloacae (55%). 50% were nosocomial and the most frequent origen was biliary tract (35,8%). 35% met sepsis criteria. 30% of cases presented cefotaxim resistance. Empiric and definitive antibiotic treatment was prescribed according IDSA guidelinesi n 34% and 91% of cases, respectively.. Death at 30 days was 6% and a combination outcome of death and relapse of infection at 30 days was 11,9%. Definitive antibiotic treatment adequacy according to IDSA guidelines was associated with lower mortality and relapse at 30 days (OR 0,04; IC95 0,003-0,6; P=0,02). Antimicrobial stewardship team did an intervention in 34% cases. This intervention was associated with a trend toward of lower mortality and relapse (4% vs 15%, P=0,2), a trend toward of higher IDSA guidelines adequacy (100% vs 86%, P=0,08), and a higher switch to oral treatment (78% vs 52%; P=0,03). Conclusion Adequacy of definitive antimicrobial treatment in high risk AmpC producing Enterobacterales BSIs according to IDSA guidelines was associated with a better outcome. Antimicrobial stewardship is desired for management of these patients. Disclosures All Authors: No reported disclosures

Abstract Background Lymphocytic choriomeningitis virus (LCMV) infection in immunocompromised hosts can result in disseminated disease, meningoencephalitis, and death. Published cases in transplant recipients have been traced to transmission from infected donors. We report 2 cases of serious, non–donor-derived LCMV infection in solid organ transplant recipients. Methods Initial identification of LCMV infection was done by using metagenomic next-generation sequencing (mNGS). Subsequent evaluations and confirmatory testing involved molecular diagnostics, serology, and phylogenetic analysis. A detailed epidemiologic investigation was conducted. Results LCMV was detected by mNGS in 2 solid organ transplant recipients from distinct donors. A heart transplant recipient (from donor 1) died of progressive, disseminated LCMV infection, while a kidney transplant recipient (from donor 2) with LCMV meningoencephalitis survived. A multistate laboratory and epidemiologic investigation of both donors and all their organ recipients was initiated. Postmortem samples were obtained from both donors, and pretransplant and/or posttransplant samples were obtained from 5 of the 6 organ recipients. mNGS, serologic, and real-time reverse-transcription polymerase chain reaction testing confirmed LCMV infection in both solid organ transplant recipients. Epidemiologic investigation revealed significant pretransplant rodent exposures for both LCMV-infected recipients. Laboratory studies for the other organ recipients from both donors were negative for LCMV infection. Conclusions Our investigations suggest that LCMV infection in 2 solid organ transplant recipients originated from rodent exposure preceding transplantation and were not donor derived. Although uncommon, healthcare providers should be aware of LCMV-associated serious and life-threatening illness in immunocompromised hosts. Diagnostic modalities are limited to reference laboratories.

Despite the high initial responses to chimeric antigen receptor T (CART) cell therapy, most patients relapse within the first 1-2 years. T cell quality influences the success of CART cell therapies greatly, and T cells from cancer patients are prone to transition into dysfunctional states, such as exhaustion or senescence. The role of exhaustion in CART cell failures has been studied extensively; however, the role of T cell senescence has remained mostly unexplored. In this study, we aimed to determine the development of CART cell senescence and its impact on CART therapeutic efficacy. First, we studied the development of CART cell senescence using an in vitro model to induce CART cell dysfunction. Here, we cyclically activated CD19-directed chimeric antigen receptor T (CART19) cells (either costimulated via 4-1BB (BBζ) or CD28 (28ζ)). Activation cycles are designed to mimic recurrent activation of CART cells to study the impact of T cell activation on CART cell fates throughout treatment. We added a rest time in between activation cycles to focus on senesced CART cell populations since, unlike exhaustion, senescence is irreversible even after rest. We examined CART immunophenotype, cell cycle regulators, transcriptomic profile, senescence marker gene expressions and T cell effector functions on days 0 (D0-T cell), 8 (D8-baseline CART), and 15 (D15-CART cell after one activation/rest cycles). Following an activation/rest cycle, T cell exhaustion markers CTLA4, LAG3, and PD1 returned to basal levels after an initial increase due to activation, while only TIM-3 levels remained elevated (BBζ: p=0.0090, 28ζ: p=0.0394). Increased TIM-3 expression is associated with T cell senescence, which prompted us to further investigate the development of a senescence phenotype. We found a prominent T cell senescence phenotype in BBζ compared to 28ζ, as evident by increased expression of p53 (BBζ: p=0.0248), p21 (BBζ: p=0.0483), CD27 (BBζ: p=0.0080), CD28 (BBζ: p=0.0327), uPAR (BBζ vs. 28ζ: p&lt;0.0001), and KLRG1 (BBζ vs. 28ζ: p=0.0029) in recurrently activated-rested CART cells. Next, we evaluated the transcriptomic signature of recurrently activated-rested CART cells. Gene set enrichment analysis (GSEA) indicated enrichment of gene sets related to senescent T cells as well as senMayo, a novel gene set which is reported to be selectively enriched in senescing cells or tissues, in BBζ, but not in 28ζ, compared to T cell D0 or in BBζ D15 compared to 28ζ D15 (p=0.00014 and p=0.089, respectively). MYC-related gene sets were found to be significantly enriched in recurrently activated/rested BBζ and depleted in 28ζ (p&lt;0.1). MYC expression is increased in BBζ (p= 0.0010) while decreased in 28ζ (p=0.0036) upon recurrent activation and is higher in BBζ (D8: p=0.0018, D15: p= 0.0022) compared to 28ζ at indicated time points by qPCR. Given these results, we induced senescence in CART cells using two alternative strategies: MYC-T58A activation (oncogene-induced senescence) and irradiation. Senescence induced by MYC-T58A overexpression ameliorated only BBζ killing (p=0.0057), whereas senescence induced by irradiation improved 28ζ killing (p= 0.0086), indicating versatile impact of senescence on treatment outcome diverse CART cell therapies. Finally, analysis with two independent patient data sets correlated the emergence of senescence with contradicting clinical outcomes to BBζ and 28ζ treatments. The presence of senescent 28ζ cells in the peripheral blood of 28ζ-treated patients was reported to be associated with complete response in the clinic in an independent analysis. In another cohort, 28ζ-treated patients with higher senescence score were correlated with longer disease-free survival (p=0.0029), while senMayo gene set enrichment in BBζ-treated patients was associated with non-response in the clinic (p=0.014). In the same cohort, MYC-related gene sets-the same genes sets enriched in our recurrently activated/rested BBζ-are also enriched in nonresponsive BBζ-treated patients. In summary, our study indicates that (i) CART cells are susceptible to a state of senescence, as demonstrated using three independent approaches (repeated activation/rest, irradiation, and MYC modulation), (ii) CART senescence is more prominent in BBζ than 28ζ, and (iii) senescence is associated with worse outcomes following BBζ but not 28ζ treatment.

Background Follicular lymphoma (FL) is a generally indolent disease where a watch and wait strategy is standard in asymptomatic patients (pts) with a low tumor-burden. Harnessing antitumor immunity through an anti-tumor immunization strategy at this stage may delay or avoid the subsequent need for more toxic and complex therapies. EO2463 is a therapeutic vaccine designed from non-self protein sequences, derived from gut bacteria, including 4 HLA-A2 synthetically produced 9-mer CD8 cytotoxic T cell epitopes, exhibiting molecular mimicry with specific epitopes on the B cell markers CD20, CD22, CD37, and CD268 (BAFF-receptor). Additionally, EO2463 contains a CD4 helper epitope UCP2 derived from hTERT. The compound expands pre-existing memory CD8 T cells recognizing the non-self protein sequences from gut bacteria which can then cross-react with the selected B cell antigens on tumor cells. EO2463 is being used to drive anti-tumor immunity against B cell malignancies, and has demonstrated long-lasting, specific CD8-memory T cell responses and clinical activity in relapsed/refractory FL and marginal zone lymphoma (MZL) [J Clinical Oncol 2024, 42 (S16), 7058]. Furthermore, CD8 T cells expanded from samples of patients treated with EO2463 can kill HLA-A2 expressing lymphoblastoid cell lines presenting the B cell targets [Hematological Oncol 2023, 41 (S2), 581-582]. Methods The current report describes Cohort 2 of trial EONHL1-20/SIDNEY (NCT04669171) and includes pts with newly diagnosed, previously untreated FL, grade 1-3A, HLA-A2, and not in need of treatment. Pts receive EO2463 (300μg/peptide) SC with adjuvant Montanide ISA 51 VG, q2 weeks (w) x 4, then q4w, for a total of 12 doses (39w; PET-CTs at w6, w19, and w42). Planned accrual for this cohort is 25 pts. Immune responses were assayed on thawed pt peripheral blood mononuclear cells by flow cytometry and EO2463 peptide specific tetramers or by IFN-γ ELISPOT (assaying responses against 9-mer peptides from CD20, CD22, CD37, and CD268; and from peptides of EO2463) without any proceeding in vitro stimulation (ex vivo). Results As of June 2024, 15 pts had started study treatment. Median age was 62 (range 55-66) year, 7 male and 6 female, 2 pts Ann Arbor stage I/II, 5 stage III, and 8 stage IV. Ten of 15 pts were still on treatment; median treatment duration was 18.4 weeks (range 5-39 w) for all pts. Among 13 evaluable pts, best responses by PET-CT using Lugano criteria were 1 pt CR, 5 pts PR (46% objective responses (OR)), 3 pts SD, and 4 pts PD. Of those with PD per Lugano, 2 had isolated increases in FDG-uptake without increase in lesion size/number at w6 and both remain on treatment (per protocol based on LYRIC criteria). OR was first noted w6 in 3 pts and w19 in 3 pts; duration of response is not evaluable at this time due to short follow-up. The pt with CR had isolated increases in FDG-uptake at w6, PR at w19, and CR at w35. Anti-EO2463 immune responses were observed in 4 of 5 tested pts at the 1st testing timepoint (w5) and onwards (currently longest tested up until w31). In an exploratory analysis, the percentage of EO2463 peptide specific CD8 T cells measured by tetramers seemed linked to clinical response (OR 3 pts vs non-OR 2 pts; 2-sided T-test, p=0.02; range of percentages in pts with OR 0.85%-1.39% of all CD8 T cells in peripheral blood, range in pts with non-OR 0.17%-0.27%). Functionality and cross-reactivity of responses were shown by IFN-γ ELISPOT using 9-mer peptides corresponding to the B cell targets in 4 tested pts. Expanded antigen-specific CD8 T cells displayed a memory phenotype; effector/memory (TEM), and terminally differentiated effector memory CD8 T cells (TEMRA). The most common related AEs were grade 1 (7 pts) and grade 2 (5 pts) local administration site reactions (mainly erythema, pruritus, and induration). Other related AEs in &gt; 1 pt were grade 1 headache (2 pts) and grade 1-3 fatigue/asthenia (3 pts). Asthenia lasting 2 days was the only related grade 3 adverse event (AE). Conclusions EO2463 monotherapy is associated with a very manageable safety profile and appears to demonstrate meaningful single-agent efficacy in FL. Consistent with the preclinical hypothesis, expansion of specific CD8 memory T cells may be associated with response. Results will be expanded at the meeting. Study EONHL1-20/SIDNEY also includes cohorts, not covered in this abstract, exploring EO2463 plus rituximab for 1st line FL/MZL, and EO2463 plus lenalidomide/rituximab in relapsed FL/MZL.