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BACKGROUND: Mechanisms of benefit with SGLT2is (sodium-glucose cotransporter-2 inhibitors) in heart failure (HF) remain incompletely characterized. Dapagliflozin alters ketone and fatty acid metabolism in HF with reduced ejection fraction though similar effects have not been observed in HF with preserved ejection fraction. We explore whether metabolic effects of SGLT2is vary across the left ventricular ejection fraction spectrum and their relationship with cardiometabolic end points in 2 randomized trials of dapagliflozin in HF. METHODS: Metabolomic profiling of 61 metabolites was performed in 527 participants from DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) and PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction HF; 12-week, placebo-controlled trials of dapagliflozin in HF with reduced ejection fraction and HF with preserved ejection fraction, respectively). Linear regression was used to assess changes in principal components analysis–defined metabolite factors with treatment from baseline to 12 weeks, as well as the relationship between changes in metabolite clusters and HF-related end points. RESULTS: The mean age was 66±11 years, 43% were female, and 33% were self-identified as Black. Two principal components analysis–derived metabolite factors (which were comprised of ketone and short-/medium-chain acylcarnitines) increased with dapagliflozin compared with placebo. Ketosis (defined as 3-hydroxybutyrate >500 μM) was achieved in 4.5% with dapagliflozin versus 1.2% with placebo ( P =0.03). There were no appreciable treatment effects on amino acids, including branched-chain amino acids. Increases in several acylcarnitines were consistent across LVEF ( P interaction >0.10), whereas the ketogenic effect diminished at higher LVEF ( P interaction =0.01 for 3-hydroxybutyrate). Increases in metabolites reflecting mitochondrial dysfunction (particularly long-chain acylcarnitines) and aromatic amino acids and decreases in branched-chain amino acids were associated with worse HF-related outcomes in the overall cohort, with consistency across treatment and LVEF. CONCLUSIONS: SGLT2is demonstrate common (fatty acid) and distinct (ketogenic) metabolic signatures across the LVEF spectrum. Changes in key pathways related to fatty acid and amino acid metabolism are associated with HF-related end points and may serve as therapeutic targets across HF subtypes. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique Identifiers: NCT03030235 and NCT02653482.

ABSTRACTApheresis is performed worldwide for an increasing number of indications. The development of common data elements (CDE) for apheresis related areas may facilitate conduct of new research, enhance quality initiatives including benchmarking, and improve patient care. This report describes the systematic development of the Uniform Apheresis Case Report Form (UACRF) as part of the Apheresis in the United States (ApheresUS) program. A consensus panel of 17 diverse experts in apheresis, related specialties, and electronic case report form (eCRF), and database development was assembled. The panel met via online conferencing from November 17, 2020 to December 1, 2021. A draft document was posted online for public comment from October 11, 2021 to November 10, 2021. Feedback was collected using an online survey tool. The consensus panel revised the UACRF. This version was converted to an eCRF with additional changes made to improve usability in this format. The final version of the UACRF was created on August 24, 2023. The UACRF contains 16 modules: procedure and subject eligibility, patient demographics, general procedure information, laboratory parameters, vascular access, common procedure elements, eight procedure specific modules (mononuclear cell collection and seven therapeutic modalities), outcomes, and site information. A total of 137 data elements were created, including 57 with one or more subelements. The UACRF is the first systematic attempt to develop CDE for therapeutic apheresis and white blood cell collections. Further validation of the UACRF is necessary to confirm the tool's ability to collect the relevant data elements and determine the usability of the form.

Background Transcranial Doppler (TCD) is a non-invasive, bedside tool that allows for real-time monitoring of the patient’s hemodynamic status following mechanical thrombectomy (MT). This systematic review and meta-analysis aims to evaluate the predictive value of TCD parameters following successful MT (Thrombolysis in Cerebral Infarction 2b–3). Methods In July 2024, we searched PubMed, Embase, and Scopus, to identify observational studies in which TCD parameters were measured within 48 hours of MT. Using random-effects models, we compared four TCD parameters (mean flow velocity (MFV), MFV index, pulsatility index (PI), and peak systolic velocity (PSV) among groups with vs without hemorrhagic transformation (HT) and favorable vs poor functional recovery (modified Rankin Scale 0–2 vs 3–6). Results Eleven studies comprising 1432 patients (59% male; mean age range: 63–73 years) were included. The MFV and MFV index were higher in patients with HT (Hedges' g=0.42 and 0.54, P=0.015 and 0.005, respectively). Patients with MFV index ≥1.3 showed a higher risk of all HT (RR 1.97; 95% confidence interval (CI) 1.28 to 3.03, P=0.002), symptomatic HT (RR 4.68; 95% CI 1.49 to 14.65, P=0.008), and poor functional status at 90 days (RR 1.65; 95% CI 1.27 to 2.14, P=0.029), respectively. There was no difference in mean PSV (P=0.1) and PI (P=0.3) among groups with and without HT. Conclusion This study underscores the prognostic value of the MFV index in predicting HT, symptomatic HT, and poor functional recovery after successful MT in the anterior circulation. Large-scale, multi-center studies are necessary to confirm these findings and to validate the MFV index as a reliable predictor for improving post-thrombectomy care.

Abstract Background and Objectives Gastric varices (GVs) are associated with a higher risk of uncontrolled bleeding and death when compared with esophageal varices. While endoscopic glue injection therapy has been traditionally used for secondary prophylaxis in GV, data regarding primary prophylaxis continue to emerge. Recently, EUS–guided therapies have been used in GV bleeding. Methods We conducted a comprehensive search of several major databases from inception to June 2022. Our primary goals were to estimate the pooled rates of treatment efficacy, GV obliteration, GV recurrence, and rebleeding with EUS-guided therapy in primary and secondary prophylaxis. Overall adverse events and technical failures were assessed. Random-effects model was used for our meta-analysis, and heterogeneity was assessed using the I 2 % statistics. Results Eighteen studies with 604 patients were included. In primary prophylaxis, pooled rate of GV obliteration was 90.2% (confidence interval [CI], 81.1–95.2; I 2 = 0). With combination EUS–glue and coil therapy, the rate was 95.4% (CI, 86.7%–98.5%; I 2 = 0). Pooled rate of posttherapy GV bleeding was 4.9% (CI, 1.8%–12.4%; I 2 = 0). In secondary prophylaxis, pooled rate of treatment efficacy was 91.9% (CI, 86.8%–95.2%; I 2 = 12). With EUS-glue, EUS-coil, and combination EUS–glue and coil, the rates were 94.3% (CI, 88.9%–97.1%; I 2 = 0), 95.5% (CI, 80.3%–99.1%; I 2 = 0), and 88.7% (CI, 76%–95.1%; I 2 = 14), respectively. Pooled rate of GV obliteration was 83.6% (CI, 71.5%–91.2%; I 2 = 74). With EUS-glue, EUS-coil, and combination EUS–glue and coil, the rates were 84.6% (CI, 75.9%–90.6%; I 2 = 31), 92.3% (CI, 81.1%–97.1%; I 2 = 0), and 84.5% (CI, 50.8%–96.7%; I 2 = 75), respectively. Pooled rates of GV rebleeding and recurrence were 18.1% (CI, 13.1%–24.3%; I 2 = 16) and 20.6% (CI, 9.3%–39.5%; I 2 = 66), respectively. Conclusion Our analysis shows that EUS-guided therapy for GVs is technically feasible and clinically successful in both primary and secondary prophylaxis of GV.

PURPOSE On the basis of the results of the ZUMA-3 trial, brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, gained US Food and Drug Administration approval in October 2021 for adults with relapsed/refractory (R/R) B-cell ALL (B-ALL). We report outcomes of patients treated with brexu-cel as a standard therapy. METHODS We developed a collaboration across 31 US centers to study adults with B-ALL who received brexu-cel outside the context of a clinical trial. Data were collected retrospectively from October 2021 to October 2023. Toxicities were graded per American Society for Transplantation and Cellular Therapy guidelines for cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). RESULTS At the time of data lock, 204 patients had undergone apheresis and 189 were infused. Median follow-up time was 11.4 months. Forty-two percent of patients received brexu-cel in morphologic remission and would have been ineligible for participation in ZUMA-3. After brexu-cel, 151 achieved complete remission (CR), of which 79% were measurable residual disease (MRD) negative remissions. Median progression-free survival (PFS) was 9.5 months and median overall survival was not reached. Grade 3-4 CRS or ICANS occurred in 11% and 31%, respectively. In multivariable analysis, patients receiving consolidative hematopoietic cell transplantation (HCT; hazard ratio, 0.34 [95% CI, 0.14 to 0.85]) after brexu-cel had superior PFS compared with those who did not receive any consolidation or maintenance therapy. CONCLUSION Similar to ZUMA-3, high rates of MRD-negative CR were observed after brexu-cel treatment for R/R B-ALL. The use of HCT as consolidation after brexu-cel resulted in improved PFS.

Abstract BACKGROUND High-grade glioma (HGG) is the most common and aggressive form of primary brain cancer with poor prognosis. Standard of care surgery employs Magnetic Resonance Imaging (MRI) to identify the contrast enhancing (CE) core for resection, leaving behind an unresected non-enhancing (NE) invasive rim of tumor which borders healthy brain tissue and invariably contributes to recurrence. Recent multi-omic analyses identified predominant neuronal and immune signatures within NE tumor; understanding these signatures could provide key insights to combatting recurrence and improving patient outcomes. To this end, we utilized a novel graph database method to integrate multi-omic data from a unique dataset of multi-regional spatially-localized biopsies from the CE core and invasive NE rim from a large cohort of patients with HGG. MATERIAL AND METHODS 159 IDH-wildtype tumor biopsy samples from the NE and CE regions of 74 glioma patients were profiled by bulk RNA sequencing. Differentially expressed genes (DEG) (n=1159) across NE and CE samples were selected using EdgeR. Samples were hierarchically clustered (method = median) for each DEG and represented as nodes in a Neo4j graph network. Edges were generated between nodes sharing ≥ 1 sample. Modularity optimization was used to identify communities of densely connected nodes. Genes occurring exclusively within NE communities were localized by cell type using external single-cell RNA sequencing datasets and selected as candidate source nodes for NE network random walks. RBFOX1 was selected as a source (walk length = 5; 10,000 walks/source node). Random walks traversing samples with significantly elevated RBFOX1 expression (one-tailed test) were kept for analysis. Genes occurring at significantly high frequency (one-tailed test) within random walks were ranked by correlation with RBFOX1 expression in NE samples and analyzed by gene set enrichment analysis (GSEA) for biological processes using clusterProfiler. RESULTS RBFOX1, a neurodevelopmental regulator, was upregulated (logFC = 1.85) in NE samples and uniquely occurred in NE communities. We show RBFOX1 is differential expressed in the aggressive Neuronal glioma subtype and enriched in neuroepithelial/astrocyte subpopulations across single cell HGG datasets. NE network random walks identified 201 DEGs associated with RBFOX1. GSEA revealed upregulation of neurodevelopmental signatures and downregulation of proliferative pathways amongst RBFOX1’s network. CONCLUSION RBFOX1’s genetic network within NE tumor represents neurodevelopmental processes potentially underlying glioma invasiveness within the NE region. As such, understanding the mechanistic role of key genes within the RBFOX1 network may provide insight into novel strategies for targeting these invasive cells within an aggressive subtype of glioma in the NE rim.

Abstract BACKGROUND Glioblastoma (GBM) is the most common primary brain malignancy in adults. Standard of care (SOC) for suspected GBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. Imvax has utilized its Goldspire™ platform to create IGV-001, an autologous biologic-device combination product for the treatment of newly diagnosed GBM (ndGBM). IGV-001 consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA (IMV-001), irradiated and administered via biodiffusion chambers implanted in the abdomen. Together, these components stimulate immunogenic cell death and antigen release. In a phase 1b study in patients with ndGBM, IGV-001 was well tolerated without unexpected adverse events. Multiple efficacy signals were also observed, including significant improvements in progression-free survival, overall survival, radiographic evidence of tumor response, and changes in immune response biomarkers. A phase 2b randomized, multicenter, double-blind, placebo-controlled study to assess the safety and efficacy of IGV-001 in patients with ndGBM (ClinicalTrials.gov identifier: NCT04485949) is ongoing. Here, we present the first safety data from the study. MATERIAL AND METHODS After surgical resection, patients are treated with IGV-001 or placebo followed by SOC. The study will enroll approximately 93 patients at 20 sites in the United States, with a 2:1 randomization favoring IGV-001. The primary outcome is progression-free survival, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include overall survival, defined as the time from randomization to death due to any cause, and safety. RESULTS As of February 2, 2024, a total of 72 patients have been randomized and 69 have been implanted with IGV-001 or placebo plus SOC. The median age was 60.0 years (range, 24-70 years). Most randomized patients (76.4%) were 51-70 years of age, and the male:female ratio was 2.27. A total of 39/45 (86.7%) patients with enough follow-up time, initiated treatment with concurrent radiation and temozolomide. A total of 9/72 (12.5%) randomized patients discontinued treatment, including 7 patients who discontinued during the SOC treatment period. No patients discontinued treatment for adverse events, protocol deviations, or death. A total of 11/72 (15.3%) randomized patients discontinued the study after randomization. CONCLUSION To date, the review of blinded safety data did not show any emerging risk and supports that there is no change to the benefit-risk profile of treatment with IGV-001 versus placebo. The data will be updated before presentation.