Citations

Lay Summary Accurately differentiating actual tumor progression from treatment-related changes, such as pseudoprogression or radiation-induced injury, remains one of the most critical diagnostic challenges in neuro-oncology for both primary and secondary brain tumors. Conventional MRI often lacks specificity because it primarily reflects blood-brain barrier disruption rather than viable tumor tissue. Consequently, advanced techniques like perfusion-weighted MRI and amino acid PET have gained significant attention. While perfusion-weighted MRI provides essential insights into blood flow and is widely available, accumulating evidence suggests that amino acid PET can be more reliable in identifying treatment-related changes. Since both modalities offer complementary information, there is an ongoing debate regarding their relative roles and the optimal way to integrate them into clinical practice. Combining these tools aims to provide more reliable diagnoses, ultimately preventing unnecessary interventions and ensuring that true tumor growth is detected as early as possible.

Background: Recent reports suggest increasing trends in injuries, primarily among pitchers and upper extremity injuries, among Major League Baseball (MLB) and Minor League Baseball (MiLB) players. Accordingly, an updated comprehensive report on injury epidemiology in professional baseball is needed. Purpose: To (1) update the literature with a comprehensive epidemiological report of all injuries in MLB and MiLB; (2) provide a detailed breakdown of characteristics of the top 50 injuries; and (3) analyze long-term trends in injuries and days missed (DM) over time. Study Design: Case Series; Level of evidence, 4. Methods: The MLB Health and Injury Tracking System was used to identify injuries in MLB and MiLB players from 2011 to 2023. The inclusion criteria consisted of injuries occurring during spring training, regular season, or postseason activities that resulted in ≥1 DM from play. Basic and advanced player and injury characteristics were analyzed—including a list of the top 50 most common injuries. Results: From 2011 to 2023, a total of 83,215 musculoskeletal injuries occurred among MLB and MiLB players, resulting in 1,280,887 total DM, with a mean (median) DM per injury of 18 (11). The upper extremity accounted for 46% of injuries, and the lower extremity for 30%. The most common injury was hamstring strains (n = 6603; 7.9%); hamate fractures had the highest rate of surgery (81%); and elbow medial ulnar collateral ligament injury resulted in the highest DM (583,070 days). From 2011 to 2023, a significant increase was observed in the number of annual injuries (excluding 2020) ( P = .028) and injuries per game ( P = .003). However, 2018 and 2019 saw the highest number of injuries, and injuries did not rise after 2020. Conclusion: The annual number of injuries and rate of injuries per game increased significantly from 2011 to 2023; however, injuries did not increase over the final 3 years of the study (2021 to 2023). The percentage of overall injuries was dominated by upper extremity injuries among pitchers, although hamstring strains were the most common injury type overall.

PURPOSE GBM AGILE (ClinicalTrials.gov identifier: NCT03970447 ) is a phase II/III Bayesian adaptive platform registration trial testing multiple arms against a common control; the primary end point is overall survival (OS). Regorafenib, a multikinase inhibitor, showed OS benefit in recurrent (RD) glioblastoma in the phase II REGOMA trial and entered GBM AGILE as the first investigational arm. METHODS Patient subtypes included in the regorafenib arm of GBM AGILE were newly diagnosed unmethylated (NDU) and RD glioblastoma. Prospective defined sets of subtypes, or arm signatures, were NDU, RD, and all (NDU + RD). As the first investigational arm in GBM AGILE, regorafenib was equally randomized to the control arm. Treatment in the control arm is temozolomide + radiotherapy (in newly diagnosed) or lomustine (in RD). Efficacy was assessed by OS hazard ratio (HR), arm/control, and demonstrated when the Bayesian probability of benefit (HR <1.00) was ≥98%. Analysis was performed monthly for limited efficacy, which occurs when the Bayesian predictive power is <25% for all signatures, and determines stopping enrollment. Follow-up continued for 12 months after accrual stopped. RESULTS When the predictive power was <25% in all predefined signatures for regorafenib, accrual stopped for limited efficacy. The final analysis did not demonstrate OS improvement in the regorafenib arm in RD nor NDU glioblastoma. Median HRs were 1.05 (NDU), 1.07 (RD), and 1.07 (all) with final probabilities of benefit (HR <1.00) of 0.421 (NDU), 0.312 (RD), and 0.296 (all). Regorafenib was associated with increased toxicity relative to control. CONCLUSION GBM AGILE did not show superiority of regorafenib over control in RD (lomustine) or NDU (temozolomide + radiotherapy) glioblastoma, yet caused increased toxicities. Regorafenib has been removed from National Comprehensive Cancer Network guidelines as a treatment option for RD.

Abstract Hairy cell leukemia (HCL) and HCL variant (HCLv) are distinct, rare, and chronic splenic B-cell lymphomas/leukemias that partially overlap in clinicopathologic presentation but differ in genetic basis, prognosis, and management. HCL is caused by the BRAF-V600E kinase–activating mutation in &gt;95% of the patients, usually has excellent responses to chemotherapy with purine analogues, and is also amenable to BRAF inhibitor–based targeted treatments. In contrast, HCLv lacks BRAFV600E mutation, requires combined therapy with purine analogues in addition to rituximab, and generally shows less durable responses. Here, an international team of hematologists, experts on these rare diseases, was convened by the Hairy Cell Leukemia Foundation to update the previous guidelines (published in 2017) by providing a summary of current methods to diagnose and manage patients with HCL and HCLv as well as a prospective on newer targeted therapies to further improve outcomes.

Abstract INTRODUCTION Anti—amyloid‐β (Aβ) therapies are reshaping Alzheimer's disease (AD) management. Understanding changes in real‐world patterns of diagnostic testing and infusion chair usage is essential for optimizing access to care. METHODS Retrospective analysis of Mayo Clinic enterprise electronic health records (Jan 2019–Mar 2025) assessed trends in AD‐relevant brain imaging, fluid biomarkers, apolipoprotein E (APOE) testing, and lecanemab infusions. Rates of amyloid‐beta (Aβ) positivity by sex and age, APOE genotype frequencies, and lecanemab treatment initiation and discontinuation were evaluated. RESULTS Following national insurance coverage changes, lecanemab infusions grew by 110 infusions per quarter to 605 in Q1 2025. Aβ positron emission tomography scans increased (+22/quarter), cerebrospinal fluid biomarker orders declined (−25/quarter), and plasma p‐tau 217 orders rapidly increased (+238/quarter). Females were more likely to be Aβ positive ( p < 0.006). APOE ‐ε4 homozygotes were less likely to initiate lecanemab (HR = 0.11, p < 0.001). DISCUSSION The adoption of anti‐Aβ therapies coincided with a rapid shift in diagnostic workflows.

Abstract Background: Cellular immunotherapy has transformed cancer treatment, but success in solid tumors remains limited by long manufacturing times, high costs, and the need for viral vectors that permanently modify DNA. To address this, we examined electroporation (EP) and mechanoporation (MP) approach to transfect T cells with mRNA to enable the development of a bedside immune cell editing platform. NKG7, natural killer cell granule-7, was previously demonstrated to play key function in activating T-cell cytotoxicity function. mRNA transfection of T cells with NKG-7 can increase these cells’ anti-tumor cell killing. We examine EP and MP methods for NKG7 transfection in primary peripheral blood mononuclear cells (PBMCs) from healthy donors. Method: Synthetic Clean Cap mRNAs encoding NKG7 or NKG7 with membrane-bound cRNA IL-2 were introduced into PBMCs by electroporation (MaxCyte) or mechanoporation (Portal Bio). T cell expression of NKG7 and IL-2 were analyzed by CytoFlex flow and Kaluza. Result: The yield at EP and MP were comparable at 0.615+/-0.09% and 0.597+/-0.16%, respectively. Viability were high at above 80% for 3 days after EP and MP. NKG7 and NKG7+cIL-2 mRNA transfection led to different NKG7 expression kinetics in T-cells and between EP and MP. With EP, CD4 T-cells showed an increase in NKG7 expressions with the highest MFI ratio (NKG7 MFI/ IgG MFI) compared to mock EP at Day 1 for the NKG7 -only EP (1.25 ± 0.38) and at Day 2 for NKG7+cIL-2 EP (1.20 ± 0.27). CD8+ T cells displayed a similar trend, with peak NKG7 expression at Day 1 for NKG7 EP (1.22 ± 0.76) and Day 2 for NKG7+cIL-2 EP (1.21 ± 0.90). However, MP did not enhance NKG7 expression in CD4+ T cells. NKG7 expression peaked at Day 1 for both NKG7 (1.28 ± 0.42) and NKG7 + cIL-2 (1.24 ± 0.20). IL2 expression peaked at Day 1 for both EP and MP: EP, CD4+ T (91.5% ± 4.4), CD8+ T (92.7% ± 12.8); MP, CD4+ T (88.9% ± 31.7), CD8+ T (84.7% ± 9.6). Functional assays for anti-tumor cell killing of these transfected cells are currently ongoing. Conclusions: We report that EP of PBMC can transfect all cell populations. MP may yield comparable yield, viability and NKG7 expression in CD8 T cells compared to EP, but without the need to isolate CD8 T cells from PBMC. EP and MP method can be used for bedside immune cell transfection depending on the target and cell populations of interest. Citation Format: Chen Wu, Christoph Schaefers, Malvika Gupta, Kevin Regan, Zuoyi Shao, Andre De Menezes Silva Corraes, Virginia Van Keulen, Jacob Hirdler, Tobias Peikert, Timothy D. Wiltshire, Haidong Dong, Yi Lin. A non-viral mRNA engineering platform for rapid, same-day immune-cell therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5198.

Abstract Background: Pembrolizumab has been increasingly used off label for recurrent gliomas, yet biomarkers predicting response are poorly defined. Gliomas exhibit substantial molecular heterogeneity across Glioblastoma, IDH-wildtype (GBM), Astrocytoma, IDH-Mutant (A-IDHm), and Oligodendroglioma, 1p/19q co-deleted (OLIGO), which may influence immunotherapy efficacy. This study aimed to identify molecular predictors of progression-free survival (PFS) in recurrent glioma patients treated with pembrolizumab. Methods: Adults ≥18 years with recurrent glioma receiving ≥2 cycles of pembrolizumab between 2014 - 2024 were retrospectively identified across Mayo Clinic. Next-generation sequencing (NGS) reports were reviewed and archival tumor tissue resected prior to pembrolizumab initiation was analyzed when available. Comprehensive molecular profiling was performed using the Mayo Clinic Solid Tumor Panel which employs the Illumina Tru-Sight Oncology 500 High-Throughput NGS assay. Progression was assessed using RANO 2.0 criteria. Genomic alterations (clinically relevant sequences and/or copy-number variants) were evaluated using the Kaplan-Meier method, with differences in PFS compared using the log-rank test. Results: Thirty-three patients were included [median (range) age: 44.0 (21-76) years; 63.6% male]. The interval between tumor tissue sampling and pembrolizumab initiation was 9.9 (0.9-176.1) months, and median treatment duration was 2.8 (1.4-10.4) months. Median PFS for the overall cohort was 2.4 (0.8-15.2) months, and median overall survival from pembrolizumab initiation was 6.9 (0.9-48.2) months. Patients with OLIGO (n=8) had a longer PFS [4.6 (1.9-15.2) months] than either A-IDHm [n=11; PFS 2.1 (1.1-4.4) months] or GBM [n=14; PFS 2.3 (0.8-9.2) months]. Within OLIGO, CDKN2A/B heterozygous deletion (n=3) predicted a shorter PFS (3.9 vs 10.9 months; p=0.0462), while in A-IDHm, FANC mutation (n=2) was associated with a longer PFS (4.17 vs 1.61 months; p=0.0224). No significant associations with PFS were observed for other altered genes or pathways evaluated, including but not limited to Tumor Mutational Burden, EGFR, RB1, TP53, FUBP1, NF 1 or 2, PTEN, PDGFRA, PIK3CA, PIK3R1, CDK4, KRAS, MLH1, MLH2, MSH6 genomic alterations or CDKN2A/B homozygous deletion (all p&gt;0.05). Conclusions: Pembrolizumab shows limited overall efficacy in recurrent gliomas, however, exploratory analyses identified several subtype-specific genomic alterations that may correlate with PFS. These hypothesis-generating findings highlight the potential influence of underlying tumor biology on immunotherapy response and warrant further validation in larger, prospective cohorts. Citation Format: Shameel Shafqat, Muhammad Asad Maqbool, Hussam Al Kateb, Terry C. Burns, Jian L. Campian, Shannon P. Fortin Ensign, Evanthia Galanis, Julie E. Hammack, Cristaine M. Ida, Mitch L. Klebig, Timothy J. Kaufmann, Autumn C. Moon, Maciej M. Mrugala, Bryan J. Neth, Alyx B. aPorter, Michael W. Ruff, Ugur T. Sener, Wendy J. Sherman, Joon H. Uhm, Rachael A. Vaubel, Sani H. Kizilbash. Molecular correlates of progression-free survival in recurrent gliomas treated with pembrolizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5253.

Abstract Prognostic indices such as the CLL International Prognostic Index (CLL-IPI) and the International Prognostic Score for Early-stage CLL (IPS-E) can predict time to first treatment (TTFT) in patients with early-stage CLL. Their ability to predict risk of infection - a leading contributor to morbidity and mortality in CLL - remains uncertain. The CLL-TIM is a machine-learning model developed in Europe that integrates clinical, laboratory, and infection-related data to predict TTFT or infection risk within 2-years of diagnosis, Receiver Operating Characteristic - Area Under the Curve (ROC-AUC) 0.74; Agius et al., Nat Comm 11, 363 2020. We conducted the first validation of CLL-TIM in a US cohort of newly diagnosed CLL patients and compared its performance with the CLL-IPI and IPS-E indices. Adults with newly diagnosed CLL (2000-2020) were identified through the Rochester Epidemiology Project using International Classification of Disease (ICD) codes; all diagnoses were confirmed. We replicated the variable selection from the original CLL-TIM model and applied it to our cohort. The primary endpoint was a 2-year composite of either TTFT or incident infection (defined as having blood cultures drawn). Model performance was evaluated using ROC-AUC consistent with the original CLL-TIM methods. CLL-IPI and IPS-E performance was assessed using time-dependent ROC-AUC; pairwise differences in discrimination were tested using DeLong. We identified 454 CLL patients with a median age of 72 years [range, 30-97], 166 (37%) were female, Rai Stage was 0-II in 399 (92%) patients. IGHV genes were unmutated in 130/305 (42%) patients and TP53 disruption (either del17p by FISH or TP53 mutation) was present in 24/329 (8%) patients. At 2-years, 55 (12%) patients received CLL therapy, and 56 (12%) patients had an infection. The 2-year composite endpoint was observed in 94 (21%) patients. The ROC-AUC was 0.74 (95% CI 0.68-0.80) for CLL-TIM, 0.69 for CLL-IPI (95% CI 0.63-0.75, p=0.11 compared to CLL-TIM) , and 0.68 for IPS-E (95% CI 0.62-0.74, p=0.02 compared to CLL-TIM). We also evaluated the ROC-AUC using all the prognostic models for each individual endpoints. The corresponding ROC-AUC for TTFT at 2 years were 0.79, 0.74, and 0.76 for CLL-TIM, CLL-IPI, and IPS-E, respectively; and for infection at 2 years were 0.68, 0.57, and 0.52, respectively. This is the first validation of the CLL-TIM in a US-based cohort of newly diagnosed CLL patients. Although the CLL-TIM model exceeded the minimally meaningful discrimination threshold (AUC &gt;0.7) for individual patient-level risk prediction, there was no statistical difference in AUC between CLL-TIM and CLL-IPI, suggesting either model can predict the composite endpoint at 2 years. Most of the observed discrimination was driven by prediction of TTFT rather than infection, underscoring the need to develop more infection-specific risk models for newly diagnosed CLL. Citation Format: Raphael Mwangi, Tait D. Shanafelt, Soren Basnet, Emily L. West, Owen Keegan, Timothy G. Call, Yao Yuan, Bryan Alexis Vallejo, Paul J. Hampel, Lindsey E. Roeker, Yucai Wang, Saad J. Kenderian, Sara J. Achenbach, Aaron D. Norman, Kari G. Rabe, Neil E. Kay, James R. Cerhan, Curtis A. Hanson, Susan L. Slager, Sameer A. Parikh. Validation of the CLL treatment infection model (CLL-TIM) in patients with newly diagnosed chronic lymphocytic leukemia (CLL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4228.

Abstract Background: Glioblastoma recurrence is inevitable despite aggressive surgical resection of contrast enhancing (CE) tumor. Unlike the deep molecular characterization of CE glioblastoma, unresected infiltrating tumor, representing minimal residual disease (MRD) has not been well profiled. Increasingly, clinical trials are being conducted in the MRD setting for glioblastoma patients, necessitating understanding of unresected infiltrating tumor for targeted therapeutic development. Methods: Visium HD spatial transcriptomics was used to profile a cohort of newly diagnosed, treatment-naïve glioblastoma patients that underwent supramaximal resection, with both core and infiltrating in situ components. Spatial profiles generated expression signatures of infiltrative and CE tumor. For in silico prediction of therapeutics targeting the MRD, expression signatures of infiltrative and CE tumor were compared with drug perturbation signatures from the NIH L1000 database using the sRGES method to predict reversal of disease expression patterns. IC50 data from human cell lines were aggregated from the Genomics of Drug Sensitivity in Cancer or individual study data while blood-brain barrier (BBB) penetrance was predicted using the CNS-MPO approach. Findings: Infiltrative tumor expression profiles were enriched for genes corresponding to neural and oligodendrocyte progenitor like cells. In contrast CE glioblastoma displayed mesenchymal and astrocytic programs, suggesting spatial concentration of glioblastoma states within MRD and CE tumor. For CE glioblastoma, proteasome inhibitors and glucocorticoid receptor agonists were predicted to have the highest antitumor activity. In contrast, histone deacetylase inhibitors (HDACi) were highly ranked for MRD while exhibiting low predicted efficacy in CE tumor. Synergy analysis of drug candidates provided multiple dual treatment options for both the CE and MRD contexts. Conclusions: Cumulatively, these data indicate that the resected tumor does not reflect the MRD state, providing clarity on why targeted therapeutics for glioblastoma have not been particularly successful. Spatial profiling of the MRD demonstrates vulnerability to unique drug targets, which if utilized in the correct setting could confer greater survival benefit. Citation Format: Harrshavasan Congivaram, Shashwat Tripathi, Mateo Gomez, Katy McCortney, Ching Man Wai, Ruochen Du, Thomas K. Sears, Jianzhong Zhang, Daniel J. Brat, Craig M. Horbinski, Mark W. Youngblood, Jared T. Ahrendsen, Adam M. Sonabend, Stephen T. Magill, Matthew C. Tate, Maciej S. Lesniak, Sean Sachdev, Timothy Sita, Priya Kumthekar, Karan Dixit, Robin Buerki, Ditte Primdahl, Mustafa Khasraw, John de Groot, David A. Reardon, Rimas V. Lukas, Roger Stupp, Amy B. Heimberger. In silico screening of therapeutics candidates targeting minimal residual disease in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2496.