Citations

Abstract Background Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms (MPN) characterized by myeloproliferation and an increased risk of thrombohemorrhagic complications, progression to myelofibrosis (MF), and reduced overall survival. Risk-adapted management of PV/ET favors treatment with cytoreductive therapy in high-risk patients. Hydroxyurea (HU) is the most frequently utilized first-line cytoreductive agent, however pegylated interferon alpha-2a (PEG) and the more recently approved, ropeginterferon alfa-2b (ropeg-IFN), have demonstrated a potential to induce molecular responses and improve event free survival (EFS) (Gisslinger Leukemia 2023). The Myeloproliferative Neoplasms Research Consortium (MPN-RC) 111 and 112 investigator-initiated clinical trials established the efficacy and safety of PEG in both treatment naïve (n=82) and HU intolerant/resistant (n=115) patients. MPN-RC 111/112 reported results up to 36 months with a median duration of treatment of about 24 months (Yacoub Blood 2019, Mascarenhas Blood 2022). This study aims to characterize the longer-term follow-up and outcomes of 111/112 trial patients treated at our center after the study terminated. Methods This is a single center retrospective review of 34 patients with high-risk ET or PV who were treated on the 111/112 trials with PEG and continued to be followed at Mount Sinai. IRB approval was obtained prior to data capture. Therapies initiated after PEG were examined, including duration of treatment, therapy-free intervals, and response to subsequent therapies. Clinical outcomes (during/after trial enrollment) included thrombotic/hemorrhagic events, progression to MF, leukemic transformation, hematopoietic stem cell transplantation (HSCT), and death. PEG related toxicity data included development of hypothyroidism, autoimmune disease, depression/mood disorder, liver dysfunction, and ocular toxicity. Results 34 patients were included in the analysis (16 ET and 18 PV) with median age of 73.5 years. 26 (14 PV and 12 ET) were enrolled on 111 from 2012 to 2015 and 8 (4 PV and 4 ET) were enrolled on 112 from 2011 to 2016. 26 (81.3%) patients had mutations in JAK2, 3 (9.4%) in CALR, 1 (3.1%) in MPL, and 2 (6.3%) were triple-negative. At 12 months on trial, 12 (35.3%) patients achieved a complete response, 12 (35.3%) had a partial response, and 10 (29.4%) had no response to PEG. The median duration of follow up was 104.8 months after trial termination. 8 patients received no further therapy after the end of study, 12 received one subsequent therapy, and 14 received two or more subsequent therapies. 13 patients continued receiving commercial PEG or received it at some interval after study end and 2 patients were treated with ropeg-IFN. The median duration of PEG was 25.3 months on trial and 30.9 months when including those who continued on commercial PEG after trial termination. Median EFS was 140.4 months (95% CI 121.1 - Not estimated) including 5 (15%) patients with a thrombotic event, 1 (3%) with a hemorrhagic event, 8 (24%) progression to MF, 1 (3%) HSCT, 1 (3%) leukemic transformation, and 5 (15%) who died (2 second primary malignancies, 1 sepsis, 1 hemorrhage, 1 unknown). 25 of 34 patients developed toxicities potentially related to PEG therapy, including hypothyroidism (n=3), autoimmune disease (n=4), depression/mood disorder (n=10), liver dysfunction (n=13) and ocular toxicity (n=2). DiscussionPEG therapy is an effective therapy for ET and PV with the potential for durable responses. With a median follow up of more than 8 years, this single center retrospective analysis demonstrated a long EFS of greater than 11 years, accompanied by low rates of leukemic transformation and MPN-related death. There was no statistical difference in EFS based on response to PEG at 12 months on the initial 111/112 trials. The relatively short duration of PEG therapy may explain the rates of MPN-related events, including thrombosis and progression to MF. Future analyses should identify additional predictors of EFS, including duration of PEG treatment, best response to PEG at certain landmark intervals, and depth and/or duration of molecular response. This analysis also demonstrated high rates of PEG-related toxicities, although definitive causality was often difficult to determine. Additional clinical and molecular data will be available at the time of the meeting.

ABSTRACT Pharmacists play a critical role in optimizing medication use, especially in vulnerable populations such as those with chronic kidney disease (CKD). Despite strong evidence and recent guideline endorsements, many pharmacists continue to rely on the Cockcroft–Gault (C‐G) equation for medication dosing. This opinion paper issues a call to action for the widespread adoption of a race‐free, body surface area–adjusted estimated glomerular filtration rate (eGFR BSAadj ) for medication‐related decision‐making, as endorsed by the 2024 Kidney Disease: Improving Global Outcomes CKD guidelines and the National Kidney Foundation and the American Society of Nephrology Taskforce. Persistent variability in pharmacy practice, institutional protocols, and pharmacy education underscores the need for coordinated change. We urge health systems to integrate eGFR BSAadj into electronic health records and clinical decision support to enhance medication decision‐making; institutions to align protocols with contemporary eGFR‐based prescribing standards; pharmacy educators to contemporize and standardize education on kidney function assessment and medication dosing; and regulatory bodies to update licensure and board examinations. The pharmacy profession must act decisively in order to align with evidence‐based, equitable kidney‐related dosing practices and ensure optimal medication management for all patients.

Abstract Chimeric antigen receptor (CAR) T-cell therapy has emerged as a transformative treatment for hematological malignancies, yet its potential to drive lymphomagenesis poses significant clinical concerns. In this study, we investigated the mechanisms underlying CAR T-cell–associated lymphomagenesis in the gastrointestinal (GI) tract on a single case, focusing specifically on the role of integrin α4β7 expression and a predisposing somatic SH2B3 mutation. We observed oligoclonal CAR T cells homing to, and clonally expanding in, the GI tract, with the dominant expanded clone harboring both a pathogenic SH2B3 mutation and a CAR transgene integration within a TFCP2 locus. The clonal CAR T cells subsequently transitioned beyond the GI tract into the peripheral blood, suggesting a potential pathway for systemic dissemination. We found clinical, histological, and molecular evidence demonstrating the efficacy of cyclosporine in reducing the expanded malignant clone and achieving durable clinical remission for more than a year. Our findings highlight the complex interplay between CAR T-cell therapy, preexisting genetic vulnerabilities, and the GI microenvironment, emphasizing the need for vigilant monitoring and tailored therapeutic strategies to address the risks associated with CAR T-cell lymphomagenesis.

Abstract Description In the tumor microenvironment of glioblastoma, myeloid cells act as a double-edged sword—they are a major cellular component suppressing the immune response while serving as a promising therapeutic target. Our study sheds light on the voltage-gated proton channel Hv1, predominantly expressed in myeloid cells, as a pivotal regulator of their physiological functions. Elevated Hv1 expression correlates strongly with poor prognosis in glioblastoma patients, underscoring its clinical significance. Using a glioma mouse model, we demonstrated that Hv1 depletion markedly extended survival. To overcome the limitations of existing tools, we engineered novel transgenic mouse lines optimized for Hv1 research. Our findings revealed tumor-induced Hv1 upregulation, with glioma-associated macrophages identified as the principal contributors. Crucially, we identified that Hv1 in infiltrating macrophages as the major driver of survival phenotype differences. Through a multi-faceted approach combining in vivo two-photon imaging, spectral flow cytometry, and spatial transcriptomic sequencing, we discovered that Hv1 depletion limits macrophage infiltration and enhances antigen presentation, ultimately fostering a stronger adaptive immune response. These findings establish the Hv1 channel as a crucial new immune regulator within the brain tumor milieu, offering a promising target for reprogramming macrophage function to combat glioblastoma. Funding Sources Supported by NIH R35NS132326 (LJW); Mayo Clinic Cancer Center and Mayo Clinic Center for Biomedical Discovery. Topic Categories Neuroimmunology (NEUR)

Abstract Description Sequencing antigen-specific T cell receptors (TCR) remains a major technologic challenge, requiring labor- and cost-intensive single-cell approaches. We have developed a rapid and economical method for sequencing TCR mRNA from antigen stimulated peripheral blood mononuclear cells using targeted long-read nanopore sequencing with Oxford Nanopore Technologies’ (ONT) Minion sequencer. Targeted PCR amplification of TCR alpha and beta cDNA was performed with a template switching oligo (TSO). Dual unique molecular identifiers (UMI) were used for single cell, oligoclonal, or bulk cell sample specific sequence identification followed by nanopore sequencing. The reads were demultiplexed by UMIs and aligned to germline V,D, and J gene sequences from the IMGT database for identification. Error corrected sequences were then used to determine the non-templated complementarity determining region 3 (CDR3) sequence for the TCRs. From bulk PBMCs, TCR Beta Chain had 796 unique TRBV-TRBJ combination and TCR Alpha Chain had 2053 unique TRAV-TRAJ combinations. Human PBMC samples were spiked with 10% Jurkat cells and sequenced using this method for 12 hours resulting in 200K reads. After read demultiplexing, filtering (Q > 25), and alignment, it was found that 8.8% of TCR beta and 7.0% TCR alpha reads matched the Jurkat TCR sequence in the 10% spiked sample. This method provides a fast and cost-effective approach to generating antigen specific TCR sequences for downstream functional studies. Funding Sources Supported by NIH/NCI 5U01CA281660 Topic Categories Technological Innovations in Immunology (TECH)

Background: Achieving active elbow flexion in children with amyoplasia can greatly improve independence in activities of daily living. This study investigated long-term outcomes of the long head triceps transfer procedure performed for that purpose. Methods: A retrospective review of medical records was performed for all patients with amyoplasia who underwent a long head triceps transfer between January 1, 2008 and December 31, 2019. Patients with follow-up of less than 2 years were excluded. Pre- and postoperative range of motion were recorded, and patient-reported outcome measures included a visual analog scale (VAS) for function (scale 0 to 10), a VAS for overall satisfaction (scale 0 to 10), and the Pediatric Outcomes Data Collection Instrument (PODCI). Pre- and postoperative motion were compared via paired t tests. Results: Seventeen patients (25 extremities) were included. Postoperatively, average active elbow flexion was 78 degrees against gravity and 90 degrees with gravity eliminated. Patients with active elevation of the shoulder ≥90 degrees showed average active elbow flexion with gravity eliminated of 85 degrees. The mean VAS score for improvement of function was 8.3 (range, 4 to 10) from parents and 9.0 (range, 8 to 10) from patients older than 10 years. The mean VAS scores for overall satisfaction were 8.0 (range, 5 to 10) and 8.1 (range, 6 to 10), respectively. Mean PODCI scores ranged from 63 to 73 for upper extremity, 83 to 76 for transfer and basic mobility, 64 to 73 for sports participation, 83 to 95 for pain and comfort, 90 to 97 for happiness, and 74 to 79 for global function. Conclusions: The long head of the triceps transfer is an effective treatment modality for patients with amyoplasia who present with absent active elbow flexion, good passive elbow flexion, and well-defined long head and lateral heads of the triceps muscle. Overall, patients gained an active range of elbow motion with no significant functional elbow contracture and improved quality of life. However, patients with a history of elbow release surgery are at higher risk of flexion contracture and should be screened especially carefully. Level of Evidence: Level IV—case series

We sought to characterize the long-term patency of various graft types in patients undergoing coronary artery bypass grafting. A comprehensive literature search identified 139 studies including 56,827 patients who underwent isolated coronary artery bypass grafting surgery. The mean patient age was 62 years (95% confidence interval: 60–63), and 80% (95% confidence interval: 79–82) were male. Patency outcomes were analyzed for each graft type, and parametric extrapolation was performed based on mean patency and mean follow-up time per conduit. The left internal mammary artery (LIMA) demonstrated the highest mean patency at 96% with a mean follow-up of 3.2 years, followed by the right internal mammary artery (RIMA) at 94% (2.8 years), gastroepiploic artery (GEA) at 93% (1.7 years), and radial artery (RA) at 89% (3.7 years). The saphenous vein graft had the lowest mean patency at 82% with a mean follow-up of 3.5 years. Extrapolated 20-year patency rates were 77% for LIMA, 64% for RIMA, 54% for RA, 42% for GEA, and 33% for saphenous vein graft. Arterial grafts demonstrated superior long-term patency compared to vein grafts. LIMA remains the primary conduit of choice, while RIMA, followed by RA and GEA, may be appropriate secondary arterial conduits depending on patient-specific factors. Vein grafts had the poorest long-term patency.