Citations

Abstract Background Oligodendrogliomas were previously defined by histology, but since 2016, the WHO has integrated molecular signatures to create the entity of IDH-mutant 1p/19q-codeleted oligodendroglioma. These tumors harbor recurrent genetic alterations—including IDH mutations, CIC and FUBP1 loss-of-function mutations, and PI3K-activating mutations—that collectively define a genetic profile distinct from IDH-mutant astrocytoma and IDH wild-type glioblastoma. The paucity of faithful model systems has impeded progress in advancing mechanistic insights and therapeutic development for oligodendroglioma. Results To test whether recurrent mutations found in oligodendroglioma patients would drive tumor formation in mice, we utilized in utero electroporation to introduce combinations of gain- and loss-of-function mutations into the developing cortex. Initial tests that included expression of IDH-and PIK3CA-mutants with Cic and Fubp1 loss (termed Oligo) were non-tumorigenic but biased cells towards glial lineages. Introducing Cdkn2a-loss, which is normally suppressed by IDH-associated epigenetic changes in human tumors, to the Oligo combination (termed Oligo-Cdkn2a) resulted in fully penetrant tumor formation. Histopathological review showed the Oligo Cdkn2a-loss mouse model resembled grade II/III oligodendroglioma with rounded nuclei and open chromatin. If Trp53-loss is used (termed Oligo-Trp53) in place of Cdkn2a-loss, tumor histology shifts to a more astrocytic phenotype with angulated nuclei with denser chromatin, demonstrating a direct impact of Trp53-loss on histological features. Bulk RNA-sequencing verifies metabolic alterations driven by the presence of IDH-mutations in Oligo-Cdkn2a mouse models compared to an IDH wild-type GBM model. Single-cell transcriptional profiling shows that Oligo-Cdkn2a tumors contain an increased population of tumor cells that resemble more differentiated oligodendrocytes. Examination of the tumor immune microenvironment within Oligo-Cdkn2a and IDHWT GBM mouse models is being performed to determine changes in immune cell infiltration and transcriptional programs. Conclusion We have created, to our knowledge, the first murine model of IDH-mutant 1p/19q-codeleted oligodendroglioma that incorporates Cic loss. This immune-competent mouse model of IDH-mutant 1p/19q-codeleted oligodendroglioma offers a powerful new tool for interrogating tumor biology and evaluating preclinical therapeutic strategies.

Abstract Pediatric high-grade gliomas (HGGs), including diffuse intrinsic pontine glioma (DIPG), are among the most aggressive childhood brain tumors, with five-year survival rates below 10%. Current treatment options are limited to radiation, highlighting the urgent need for novel therapies. Telomere maintenance via telomerase activation is a hallmark of cancer, enabling replicative immortality. Our prior studies demonstrate telomerase activity in 73% of HGGs and 47% of DIPG, implicating telomere biology as a critical therapeutic target. 6-thio-dG (THIO) is a first-in-class telomere-targeting agent that incorporates into telomeres of telomerase-positive cells, inducing telomere uncapping, genomic instability, and apoptosis. THIO crosses the blood–brain barrier and exhibits synergy with radiation in preclinical DIPG models. Telomere dysfunction is confirmed by telomere dysfunction-induced foci (TIFs), marked by colocalization of DNA damage response proteins (ATM S1981-P, γH2AX, 53BP1) at telomeres. Historical pediatric leukemia trials established THIO’s safety profile, and recent adult studies in non-small cell lung cancer demonstrated efficacy at lower doses. As part of the biologically-guided umbrella trial CONNECT TarGeT [NCT05839379], we are developing TarGeT-H, a phase 1/2 and surgical study to evaluate THIO combined with focal radiation in pediatric, adolescent, and young adult patients with newly diagnosed HGG or DIPG harboring telomerase activation, confirmed by hTERT mRNA expression—assessed via tumor submission, profiling, and rapid central screening through TarGeT-SCR. Specific aims include: (1) determining pharmacokinetics and safety to establish the recommended Phase 2 dose (RP2D); (2) estimating efficacy by progression-free survival (HGG) and overall survival (DIPG) compared to historical controls; and (3) assessing telomere dysfunction in resected HGG tumors via TIF analysis. Up to 90 patients will receive THIO intravenously during radiation and maintenance cycles for up to two years. By leveraging a selective telomere-targeting mechanism distinct from current therapies and demonstrating synergy with radiation, THIO represents a promising strategy to improve outcomes in devastating pediatric cancers.

Abstract Background In children with non-metastatic atypical teratoid/rhabdoid tumor (ATRT), proton therapy is increasingly utilized worldwide due to the radiosensitivity of afflicted young patients. General questions persist, however, surrounding dose and volume of radiotherapy. Methods Between 2009-2024, 39 children from a single institution with non-metastatic intracranial ATRT received focal proton therapy at a median age of 2.4 years (range 0.7-19). Twenty-two patients had supratentorial tumors and 27 had gross/near total resection prior to radiation. Most common chemotherapy regimens were ACNS0333 and SJYC07 (n = 10 each) and Dana-Farber (n = 6). Four patients received consolidative high-dose chemotherapy after radiation. The median radiation dose was 50.4 Gy (range, 50.4-54). The cumulative incidence method assessed freedom from selected endpoints.The Fine-Gray method assessed the level of statistical significance between levels of selected prognostic factors. Results With a median followup of 5.2 years (range 0.5-16.2), the 5-yr overall survival, progression-free survival, and local control was 63%, 64%, and 97%, respectively. Thirteen patients developed isolated leptomeningeal failure as first site of recurrence. Only subtotal resection was significantly associated with local recurrence (100% vs 92%, p < 0.05). Patient age, tumor site, extent of resection, radiation dose, and chemotherapy regimen were otherwise not significantly associated with disease control or survival. Four patients experienced symptomatic radiation necrosis, including 1 death: Three of 4 cases received 54 Gy and consolidative intrathecal methotrexate (n = 2) or high dose ACNS0333 intravenous chemotherapy (n = 1, fatal) after radiation. The other patient received 50.4 Gy and necrosis was immediately preceded by ventriculoperitoneal shunt failure. Six patients developed hearing loss requiring aids. One patient developed radiation-induced meningioma a decade following treatment. Conclusion This represents the largest experience reporting 5-year outcomes following focal radiation in children with non-metastatic intracranial ATRT. When applied with a variety of modern chemotherapy regimens in real-world settings, focal proton therapy at a dose of 50.4 Gy may offer the best therapeutic ratio but does not eliminate serious toxicity. If avoidance of craniospinal radiation remains an ongoing priority, further improvement in survival will depend upon systemic therapy.

Abstract One of the most significant unmet clinical challenges in paediatric oncology is the development of novel therapeutic strategies for recurrent medulloblastoma (R-MB). MYC-driven MBs are defined as classically cold tumours with a low incidence of infiltrating immune cells, resulting in a therapeutic challenge. The identification of cell-cell interactions between tumour and immune cells may provide insight into critical intercellular communications and manipulations occurring within the tumour immune microenvironment (TME). We hypothesised that the key cell-cell interactions in MYC-driven primary and recurrent MB may reveal dominant immune-suppressive mechanisms and uncover targetable therapeutic vulnerabilities. Paired primary-recurrent bulk RNA-sequencing data, confirmed myeloid cells as the most infiltrating immune cell type in group3-MB and group4-MB. Comprehensive spatial phenotypic and cell-cell communication analyses corroborated this discovery, validating an increased incidence of macrophages in the matched-recurrent tumours. Subsequently, we used innovative algorithms for 10X MB single-cell data to predict interactions between tumour-cell ligands and immune-cell receptors within the TME; macrophages emerged as the core immune-cells involved in interactions throughout the TMEs, with the most significant ligand-receptor interaction and inflammatory response between MIF and CD74. In-depth immunohistochemistry analyses of primary and recurrent group3 and group4 tumours, and exhaustive tissue microarrays demonstrated expression of CD74 and MIF, with limited expression of CD74 within the brain. To investigate the therapeutic potential of CD74, we developed recurrent, immune competent MYC-driven medulloblastoma mouse models. Comprehensive deconvolution analysis confirmed the TME integrity of our models to mirror that of the human disease. Locoregional delivery and repeat dosing of a bioactive-CD74 peptide demonstrated complete tumour clearance in our immune-competent mouse models of primary and recurrent-MB, demonstrating the significant therapeutic potential of targeting the CD74-MIF axis in MYC-driven primary and recurrent MB. Key therapeutic vulnerabilities within the TME of MYC-driven MB have been identified, highlighting the CD74-MIF axis as a target for next-generation immunotherapies.

Abstract Background Approximately 12,000 adolescents and young adults (ages 15-39, AYAs) are diagnosed with a primary central nervous system (CNS) tumor each year. DNA methylation profiling has transformed CNS tumor classification by refining diagnostic accuracy and identifying biologically distinct subtypes, but its application has not been systematically evaluated in the AYA population. In this study, we examined the spectrum of CNS tumor types across age groups, with a focus on the AYA population. Methods We assembled a large dataset of CNS tumor samples with age annotations and methylation profiles matching with high confidence to a CNS tumor type using the NCI/Bethesda classifier. Prevalence of tumor type, methylation class and DNA copy number aberrations were compared across age strata (pediatric, AYA and adult). Results The cohort of 21,099 CNS tumors included 5139 tumors from AYAs (24%), which showed a mixed pattern, with tumors typical of childhood (e.g. medulloblastoma) as well as those common in older adults (e.g. glioblastoma). Several tumor types were specifically enriched in the AYA, including IDH-mutant astrocytoma, pleomorphic xanthoastrocytoma, posterior fossa group B ependymoma, and diffuse hemispheric glioma, H3 G34-mutant, among others. Distinct methylation subclasses of multiple tumor types were observed in the AYA, and patterns of genomic aberrations showed age-specific distributions. Conclusion Large-scale methylation profiling revealed unique classification patterns of CNS tumors in AYAs, with specific tumor types, subclasses, and genomic alterations enriched in this population. These data may serve as a valuable reference resource for better understanding the spectrum of CNS tumors affecting AYA patients.

Background: Anaplasmosis is an emerging tick-borne infection that typically presents as a non-specific febrile illness, with variable degrees of cytopenias and liver tests abnormalities. Severe complications remain atypical and uncommon. Case Report: We report a case of acute pulmonary embolism (PE) occurring during confirmed anaplasmosis in a 73-year-old male with no traditional thromboembolic risk factors. The patient presented with fever, constitutional symptoms, thrombocytopenia, leukopenia, and abnormal liver tests, raising suspicion for a tick-borne illness. Despite early clinical improvement on doxycycline, persistent tachycardia triggered further evaluation and uncovered an acute PE. Comprehensive workup at admission and repeated 14 months later excluded inherited and acquired thrombophilias, malignancies, autoimmune diseases, and alternative infectious etiologies. The patient was treated with doxycycline 100 mg orally twice daily for 10 days and anticoagulation with unfractionated heparin followed by 6 months of apixaban for a first episode of provoked PE. He attained complete clinical recovery without recurrence of thrombosis at the two-year follow-up. Discussion: Infectious diseases are increasingly recognized as contributors to thrombosis through inflammation-mediated hypercoagulability and endothelial dysfunction. Pulmonary involvement in anaplasmosis typically manifests as pneumonitis, pneumonia or acute respiratory distress syndrome, but thrombotic complications such as PE are exceedingly rare. This case highlights a rare but clinically significant vascular complication of anaplasmosis and underscores the importance of considering thromboembolic events in patients with persistent or unexplained tachycardia. Conclusions: As the incidence of anaplasmosis continues to rise, greater awareness of its potential cardiovascular manifestations is essential. Early recognition and prompt treatment with doxycycline remain critical, while further studies are needed to better define the thrombotic risk associated with this infection.

Background/Objectives: Tumor-infiltrating lymphocyte (TIL) therapy is an important option for patients with metastatic melanoma progressing after standard systemic therapy, but real-world data on treatment delivery, toxicity monitoring, and immune recovery remain limited. We evaluated clinical outcomes, treatment tolerance, immune reconstitution, and cardiac biomarker dynamics across three Mayo Clinic sites. Methods: We retrospectively analyzed adults with metastatic melanoma who received lymphodepleting chemotherapy followed by TIL infusion and high-dose interleukin-2 (IL-2) between April 2024 and December 2025. Clinical outcomes, treatment delivery, and adverse events were assessed. Longitudinal immune monitoring included CD4 and CD8 T-cell counts, CD4:CD8 ratio, and immunoglobulin G (IgG) at baseline and follow-up. In a prespecified cardiac sub-cohort, high-sensitivity troponin (hs-Tn) was measured during IL-2 administration to evaluate associations with cardiac events and IL-2 interruption. Results: Thirty-six patients underwent TIL infusion. The objective response rate was 50.0%, including complete responses in 13.9%, and the disease control rate was 72.2%. Median progression-free survival was 3.61 months, and median overall survival was 12.94 months. M1d disease was associated with inferior overall survival on univariable analysis (HR 6.55, 95% CI 2.03–21.17; p = 0.002), with attenuation after multivariable adjustment. Receipt of ≥3 IL-2 doses was associated with longer overall survival on univariable analysis (HR 0.20, 95% CI 0.06–0.64; p = 0.007), but this association also attenuated after adjustment. Longitudinal immune monitoring demonstrated persistent CD4 lymphopenia through 6 months, sustained inversion of the CD4:CD8 ratio, and declining IgG at months 3 and 6. In the cardiac sub-cohort (24 patients; 87 IL-2 doses), post-dose hs-Tn ≥15 ng/L was associated with clinically significant cardiac events (OR 9.6, 95% CI 1.5–60.6; p = 0.016) and IL-2 interruption (OR 3.4, 95% CI 1.1–10.7; p = 0.036). For cardiac events, hs-Tn ≥15 ng/L had 100% sensitivity and 100% negative predictive value. Conclusions: In routine practice, TIL therapy was feasible and active in metastatic melanoma. M1d disease identified a subgroup with poor survival, peri-dose hs-Tn showed promise as a tool to support safer IL-2 delivery, and prolonged CD4 suppression with IgG decline suggests that recovery after TIL therapy extends beyond initial hematologic reconstitution. These findings support prospective validation of biomarker-guided IL-2 monitoring and extended post-treatment immune surveillance.

Abstract FLASH radiotherapy shows promise in reducing normal tissue toxicity while maintaining tumor control. However, preclinical and early clinical evidence reveal biological and technical uncertainties. We review preclinical and veterinary studies, highlight unexpected toxicities, and argue that the fundamental principles of precision and safety in radiotherapy—particularly conformal treatment and ALARA—remain crucial.

Background: There is growing evidence that social determinants of health (SDOH) are associated with disparities in access to care and hand and upper extremity health. Quality measures represent an opportunity to evaluate disparities in access and outcomes that can inform improvement interventions. We performed a systematic review of evidence regarding health disparities within hand surgery and aimed to develop suitable quality measures that are clinically important, feasible, usable, and scientifically acceptable. Methods: We performed a systematic review including common hand surgery terms to identify health disparities in hand surgery related to SDOH. Candidate quality measures were constructed based upon evidence from the systematic review. A consortium of 11 US-based hand and upper extremity surgeons completed a modified RAND/UCLA Delphi Appropriateness process to evaluate the importance, feasibility, usability, and scientific acceptability of the candidate quality measures. Panelists rated each measure on a scale of 1 ( definitely not important/feasible/usable/scientifically acceptable ) to 9 ( definitely important/feasible/usable/scientifically acceptable ) in 2 voting rounds separated by a face-to-face discussion. Agreement among panelists and validity were assessed using predetermined criteria. Results: Fourteen candidate quality measures addressing health disparities were identified based on evidence from the systematic review, including time to surgery and emergency department use after hand surgery based on insurance type, clinical outcomes based on social deprivation, among others. All 14 measures were accepted. Conclusions: Fourteen candidate quality measures were identified and accepted based upon consensus to address health disparities in hand surgery, although future investigation will be needed to evaluate their effectiveness.

Neurons upregulate major histocompatibility complex class I (MHC I) during demyelination, enabling the presentation of self-antigens to cytotoxic CD8 + T cells. While this phenomenon is well described in multiple sclerosis lesions, its functional significance for disease progression remains poorly understood. Here, we test the hypothesis that neuronal MHC I expression promotes CD8 + T cell-mediated neurodegeneration in demyelinating disease. Using genetic and viral approaches to selectively ablate β ₂-microglobulin (β₂M) in neurons, we demonstrate that the loss of neuronal MHC I limits antigen presentation, attenuates the activation of neuron-antigen–specific CD8 + T cells, and reduces the recruitment of these cells to the demyelinated central nervous system (CNS). In myelin oligodendrocyte glycoprotein (MOG₃₅–₅₅)-induced experimental autoimmune encephalomyelitis, CD8 + T cell ablation during active disease limited neuronal injury and improved clinical recovery. Similarly, neuronal β ₂M ablation decreased clinical disease burden without affecting CNS T cell infiltration. Likewise, in the context of cuprizone intoxication, neuronal β ₂M deletion reduced peripheral activation and CNS recruitment of CD8 + T cells recognizing a neuron-restricted neoantigen. It protected neoantigen-expressing neurons from cognate CD8 + T cell-mediated cytotoxicity. Collectively, these findings identify neuronal MHC I–dependent antigen presentation as a driver of both the immune surveillance of neuronal antigens and neuronal injury during demyelination.