Neuro-oncology最新文献

Background: Glioblastoma (GBM), the most aggressive adult brain cancer, comprises a complex tumor microenvironment (TME) with diverse cellular interactions that drive progression and pathobiology. The aim of this study was to understand how these spatial patterns and interactions evolve with treatment.

Methods: To explore these relationships, we employed imaging mass cytometry to measure the expression of 34 protein markers, enabling the identification of GBM-specific cell types and their interactions at the single-cell protein level in paired primary (pre-treatment) and recurrent (post-treatment) GBM samples from five patients.

Results: We find a significant post-treatment increase in normal brain cells alongside a reduction in vascular cells. Moreover, despite minimal overall change in cellular diversity, interactions among astrocytes, oligodendrocytes, and vascular cells increase post-treatment, suggesting reorganization of the TME. The GBM TME cells form spatially organized layers driven by hypoxia pre-treatment, but this influence diminishes post-treatment, giving way to less organized layers with organization driven by reactive astrocytes and lymphocytes.

Conclusions: These findings provide insight into treatment-induced shifts in GBM's cellular landscape, highlighting aspects of the evolving TME that appear to facilitate recurrence and are, therefore, potential therapeutic targets.

Background: This study explored MRI characteristics at the time of tumor progression to study pathologically confirmed MT in IDHm 1p/19q-intact astrocytomas (IDHm-A) and IDHm 1p/19q-co-deleted oligodendrogliomas (IDHm-O).

Methods: N = 64 patients with initial pathological grade 2 IDH-mutant glioma diagnosis who underwent repeated tissue sampling and were classified as pathologically confirmed MT (n = 35) or non-MT (n = 29) with available presurgical anatomical (n = 64), diffusion-weighted (n = 61), and dynamic susceptibility contrast perfusion MRI (n = 53) were retrospectively studied. Measurable contrast enhancement (> 1000 mm3), tumor volume, tumor growth rate, sphericity, median apparent diffusion coefficient (ADC), and normalized relative cerebral blood volume (nrCBV) were compared between MT vs non-MT IDHm-A and IDHm-O.

Results: 81% of contrast-enhancing IDHm-A and 100% of contrast-enhancing IDHm-O demonstrated MT, while 41% of IDHm-A and 62% IDHm-O exhibited both nonenhancing tumor progression and MT. Tumor volumes were significantly larger in patients with MT compared to non-MT groups for IDHm-A (P = .02) and IDHm-O (P = .04). T2/FLAIR tumor volume growth rate was significantly higher (P = .003), nrCBV was significantly higher (P = .002), and ADC trended lower (P = .06) in MT vs non-MT IDHm-A. There were no significant differences in growth rate, ADC, nrCBV, or sphericity when comparing MT vs non-MT IDHm-O (P > .05).

Conclusions: Many MT IDHm gliomas remain nonenhancing. Growth rate, diffusion, and perfusion MRI show differences between MT and non-MT in IDHm-A but not IDHm-O, which may reflect the different tumor biology of these IDHm molecular subtypes and their need for separate imaging biomarkers. Tumor volumes can help determine MT for both IDHm-A and IDHm-O.

Background: Glycoprotein A-repetitions predominant (GARP) is a cell surface non-signaling receptor for docking and activating latent transforming growth factor beta (LTGFβ) expressed by regulatory T cells, platelets, and tumor cells. In lung and breast cancers, its expression correlates with advanced stage and poor prognosis-suggesting that GARP could act as a therapeutic target. This study examines the therapeutic impact of targeting GARP in glioblastoma (GBM) via a novel anti-GARP chimeric antigen receptor-expressing T cell (CAR-T) modality in murine models of GBM.

Methods: We examined multiple human glioma databases to correlate the expression of GARP with clinical outcomes. We then performed multi-plex imaging of human GBM samples to understand the impact of GARP expression on the tumor microenvironment (TME). Importantly, we developed a novel anti-GARP CAR-T cell strategy to treat GBM. We examine if this therapy is efficacious against orthotopic models of GBM, in both immunocompetent syngeneic and immunodeficient mice.

Results: We demonstrate that elevated GARP expression in human GBM correlates with poor overall survival, mesenchymal subtype, and gene signatures associated with angiogenesis and immune exclusion in the TME. Our novel anti-GARP CAR-T is efficacious in vitro and in vivo, against multiple preclinical models of GBM, including patient-derived xenograft (PDX) models without significant toxicity.

Conclusions: GARP-LTGFβ plays a key role in the development and prognostics of GBM, and GARP-targeted CAR-T therapy shows promising efficacy and safety in murine orthotopic GBM models. A first-in-human phase I clinical trial for patients with recurrent GBM began to enroll patients in May 2025 (NCT06964737).

Background: The 5th edition of the World Health Organization Classification of Tumors of the CNS introduced a subclassification of tumors based on key molecular markers. In adult-type diffuse gliomas, isocitrate dehydrogenase (IDH) and telomerase reverse transcriptase (TERT) promoter mutations play pivotal roles in the molecular classification. This study developed a rapid genotyping system using GeneSoC, a real-time PCR platform with microfluidic thermal cycling capable of completing 50 cycles of PCR within 20 min.

Methods: To establish optimal analytical conditions, frozen tumor tissues from 67 patients and artificial DNA vectors were analyzed using this system. This system demonstrated a detection limit of at least 5% variant allele frequency for the IDH1 R132H and TERT promoter C228T/C250T mutations. Subsequently, intraoperative testing was performed in 120 cases using this system.

Results: The sensitivity and specificity of IDH1 R132H mutation were 0.985 and 0.982, respectively, whereas those of TERT promoter C228T/C250T mutation were 1.000 and 1.000, respectively. These mutations were detected intraoperatively within approximately 25 min after tumor tissue collection. Furthermore, this assay identified tumor boundaries in an IDH-mutated glioma case, where IDH1 R132H mutations could not be detected.

Conclusions: The GeneSoC®︎-based rapid genotyping system may be effective not only for intraoperative diagnosis of diffuse glioma but also for detecting tumor boundaries.

Background: Brain metastasis (BM) in colorectal cancer (CRC) is a rare event that undermines longevity and neurocognitive function. However, the molecular basis of BM in CRC is poorly understood. We analyzed next-generation sequencing (NGS) from patients with CRC to identify genomic features associated with BM and intracranial progression (IP).

Methods: Patients with CRC who had NGS between 2014 and 2024 were included. Sequenced tumor specimens were classified by the anatomic site of biopsy as primary tumors (PT), extracranial metastases (EM), or BM. Sequenced PT specimens were compared to identify genomic differences between patients who did and did not develop BM. Among patients with BM, sequenced tumor specimens were compared to identify genomic differences by anatomic site. Sequenced BM samples were compared to identify genomic differences between patients who did and did not experience IP after BM-directed local therapy.

Results: This analysis included 5526 patients with NGS of CRC, including 269 patients with BM. PT of patients who developed BM more frequently contained alterations in the KRAS, BRAF, and SMAD4, compared with PT of patients without BM. Among patients with BM, resected BM specimens had greater tumor mutation burden, fraction of genome altered, and frequency of TP53, SMAD4, and MYC alterations, compared with extracranial tumor specimens. Patients with BM carrying SMAD4 or PI3K pathway alterations showed a trend toward earlier IP after BM-directed therapy.

Conclusions: This study identifies novel genomic associations with intracranial metastasis and progression in CRC, suggesting a potential basis for personalized clinical management.

Background: Atypical teratoid rhabdoid tumors (ATRTs) are highly aggressive pediatric central nervous system tumors defined by the inactivation of the SMARCB1 gene. Despite the identification of three distinct molecular subtypes, each defined by unique clinical and molecular characteristics, no subtype-specific therapeutic strategies are currently available. This highlights an urgent need to deepen our understanding of the cellular heterogeneity and developmental origins of ATRTs.

Methods: We generated a comprehensive single-nucleus transcriptomic atlas of ATRT samples, integrated it with single-nucleus ATAC-seq and spatial transcriptomics data, and validated our findings experimentally using patient-derived ATRT tumoroid models.

Results: Our analyses revealed distinct subtype-specific differentiation trajectories, each resembling different brain progenitor lineages. We identified key transcription factors that appear to drive these developmental pathways. Furthermore, a shared cycling, intermediate precursor cell (IPC)-like cell population, interspersed throughout tumors, was consistently present within all ATRT samples. We demonstrate that these subtype-specific differentiation pathways can be pharmacologically manipulated in patient-derived ATRT tumoroids. By directing tumor cells along their respective subtype-specific trajectories, we were able to induce a shift toward more differentiated, non-proliferative states.

Conclusions: Collectively, our findings show that ATRTs recapitulate fetal brain signaling programs in a subtype-specific manner. This work provides a framework for understanding ATRT heterogeneity and supports the feasibility of maturation-based therapeutic strategies tailored to the molecular subtype of the tumor.