Neuro-oncology最新文献

Background: Glioma patients often exhibit neurocognitive deficits across multiple domains, yet studies typically assess these impairments separately. This study explores aggregated neurocognitive functioning (NCF), identifying distinct profiles and their clinical correlates.

Methods: NCF in glioma patients with stable disease (≥ 2 months after treatment without clinical or radiological progression) was assessed across five domains: attention, information processing speed, verbal memory, working memory, and flexibility. We used hierarchical cluster analysis to distinguish neurocognitive profiles and replicated these profiles in an independent glioma cohort. Associations between neurocognitive profiles and clinical characteristics were examined using multinomial logistic regression.

Results: Four distinct neurocognitive profiles were identified in both the study (N = 108) and the validation cohort (N = 185): a preserved, memory, processing/attention, and multi-domain profile. In both cohorts, 40% of patients exhibited impaired NCF, with deficits in at least one domain observed in 44% in the study cohort and 38% in the validation cohort. In the study cohort, tumor hemisphere and prior treatment with radiotherapy or combined radio- and chemotherapy were associated with processing/attention and multi-domain profiles. In both the cohorts, the multi-domain profile showed a weak association with self-perceived NCF. No other significant associations with patient, tumor, or treatment characteristics were observed.

Conclusions: NCF in glioma patients can be classified into four reproducible neurocognitive profiles. Importantly, concurrent problems in NCF are highly prevalent. Neurocognitive profiles are associated with tumor laterality, previous oncological treatment, and self-perceived NCF, but not with other clinical characteristics.

Background: Postoperative radiotherapy improves local control after brain metastasis (BM) resection. Whole-brain radiotherapy (WBRT) reduces recurrence risk but impairs neurocognition. Hypofractionated stereotactic radiotherapy of the cavity (HFSRT) may offer equivalent tumor control with reduced toxicity. ESTRON is the first randomized trial comparing post-operative HFSRT and WBRT.

Methods: This single-center phase 2 trial randomized 56 patients with resected BM to receive HFSRT (35 Gy in 7 fractions) or WBRT (30 Gy in 10 fractions). Patients could have ≤ 10 additional unresected BMs. The primary endpoint was intracranial progression-free survival (ic-PFS). Secondary endpoints included local control (LC), overall survival (OS), leptomeningeal disease (LMD), and toxicity.

Results: Fifty-four patients were evaluable (n = 27 per arm). At 24.7 months median follow-up, 12-month ic-PFS was 44.4% (HFSRT) versus 59.3% (WBRT) (HR 1.72, P = .080). Median ic-PFS was 4.7 versus 15.0 months. LC at 24 months was 94.1% (HFSRT) versus 85.4% (WBRT) (HR 0.41, P = .433). One-year OS was 63.0% (HFSRT) versus 77.8% (WBRT), with no significant difference in median OS (17.8 vs 27.0 months; HR 1.09, P = .336). One-year risk of LMD was 27.0% (HFSRT, predominantly outside the irradiated field) versus 8.7% (WBRT) (log-rank P = .03). Treatment-related adverse events were more frequent with WBRT (115 vs 54 events), including 19% versus 11% grade 3 events, and poorer neurocognitive performance.

Conclusions: Survival was similar for HFSRT and WBRT, while WBRT trended toward better ic-PFS. HFSRT showed substantially lower toxicity and better neurocognitive preservation, however, a higher risk of LMD. Risks and benefits should be weighed individually when determining post-operative treatment for BM.

Background: Pilocytic astrocytomas (PAs) are the most common pediatric central nervous system tumors, which present with limited genetic but significant clinical heterogeneity. Current treatment strategies are partly effective, but tumors often progress, and patients experience long-term side effects, highlighting the need for additional novel therapeutic approaches. A promising alternative approach could be targeting the tumor immune microenvironment (TIME); however, a comprehensive overview of the TIME of PAs across different anatomical tumor locations is currently lacking. The aim of this study was to comprehensively characterize the cellular and transcriptional landscape of pediatric PAs.

Methods: We employed a multimodal, integrative approach using single-nucleus and bulk RNA-sequencing alongside high-dimensional immunofluorescence imaging and flow cytometry to elucidate the transcriptional landscape and cellular composition of pediatric PAs across tumor locations.

Results: Our analysis uncovered neoplastic cell transcriptional heterogeneity reflective of aberrant glial differentiation. Moreover, we provided a detailed characterization of the TIME, revealing pro-inflammatory brain-resident microglia and abundant activated monocyte-derived macrophages and T cells. Deconvolution of bulk RNA-sequencing data revealed variation in tumor and TIME composition across anatomical tumor locations. Suprasellar tumors additionally exhibited increased expression of immune-related genes compared to tumors arising in other anatomical locations.

Conclusions: Together, our multimodal in-depth characterization provides detailed insights into the transcriptional and cellular heterogeneity of pediatric PAs across distinct anatomical tumor locations, which could aid in the development of novel (immuno)therapeutic approaches.

Background: Hyper-excitable neurons are observed in the glioma brain, contributing to the notorious nature of glioma. It is well established that microglia can modulate neuronal excitability through crosstalk via P2RY12. However, the role of microglia in glioma environments remains poorly understood. Thus, this study aimed to investigate whether loss of microglial P2RY12 could contribute to hyper-excitable neurons within the glioma environment.

Methods: Using two distinct tumor models and normal Thy1-GCaMP6f mice, spontaneous neuronal activity was imaged in the peritumoral region with an in vivo 2-photon microscope. Neuronal calcium activity was then compared to the expression level of microglial P2RY12. Neuronal activity was further quantified after administering a microglial blocker and compared across different tumor models and cortical regions of a glioma mouse model.

Results: Our findings revealed that hyper-excitable neurons were exclusively observed in cortical regions surrounding glioma tissues. In the glioma environment, microglia exhibited significantly reduced expression of P2RY12, a receptor known to modulate neuronal activity via negative feedback control. In contrast, neuronal excitability and microglial P2RY12 expression relatively remained same to the control in environments of a brain metastasis model. Furthermore, blocking microglial P2RY12 enhanced spontaneous neuronal activity in both the brain metastasis model and distal regions of glioma tumors, effectively replicating the functional loss of P2RY12 observed in glioma conditions.

Conclusions: Results of this study support that neuronal hyper-excitability is a unique observation within a peri-glioma environment driven by loss of microglial P2RY12. Graphical AbstractCreated in BioRender. Park, T. (2025)https://BioRender.com/epw8o33.

Background: Glioblastoma (GBM) exhibits significant intratumoral heterogeneity. However, the presence and extent of intratumoral heterogeneity of stem-like and differentiated cell components based on methylation profiles remain poorly understood. Furthermore, the utility of integrating methylation profiles with radiomic features (radiomethylomics) for predicting these cellular states has not been explored.

Methods: We analyzed 248 samples from 133 GBM patients, including 157 samples from 42 patients whose tumors were sampled at multiple points. Two distinct methylation-based deconvolution analyses were performed to assess cellular composition. Radiomethylomic models were developed using support vector machines with features extracted from multi-parametric MRI.

Results: Multi-sampling analysis revealed that the proportion of stem-like cells among total malignant cells was homogeneously preserved within tumors. Tumors harboring a higher proportion of stem-like cells (stem-like tumors) showed significantly shorter overall survival and diminished benefits from O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Stem-like tumors showed a strong correlation with the RTK I subtype. Integrating physiological MRI features (diffusion tensor imaging and dynamic susceptibility contrast) with conventional sequences enhanced the performance of radiomethylomic models for predicting stem-like tumor status and prognostic stratification.

Conclusions: Our findings reveal a homogeneous preservation of the proportion of stem-like cells over total malignant cells within GBM, establishing its significance as a tumor-wide feature. The development of radiomethylomic signatures shows potential for noninvasive assessment of tumor stemness, ultimately facilitating personalized treatment strategies in light of the prognostic impact of the feature.

Background: A high pSTAT3 expression in reactive astrocytes surrounding brain metastases (BrM) promotes tumor growth in preclinical models. The impact of STAT3 expression on outcome of patients with BrM from breast cancer is unknown.

Methods: The expression of pSTAT3 in reactive astrocytes of 100 resected BrM from breast cancer was investigated by immunohistochemistry and correlated with molecular subtypes, risk of intracranial recurrence and progression-free survival. To explore whether clinical findings could be replicated in preclinical models, we used two human BrM cell lines (triple-negative MDA231 and HER2-positive HCC1954-), and evaluated pSTAT3 expression on established BrM.

Results: High pSTAT3 expression in reactive astrocytes was detected in 57% of BrM, and prevailed in triple-negative (80.9%) over HER2-positive (43.2%) and luminal (33.3%) metastases (P = .002). A different pSTAT3 expression was confirmed in animal models: as it was detected in 50% of reactive astrocytes in triple-negative MDA231 BrM lesions compared with 13% in HER2-positive HCC1954-BrM lesions (P = .0001). Patients with high pSTAT3 expression in BrM displayed higher intracranial recurrence rate (66.7 vs 33.3%) (P = .0353), and shorter intracranial PFS (9 months vs 28 months) (P = .0002), and this finding was significant for triple-negative patients only (P = .0008).

Conclusions: This study indicates that STAT3 expression prevails in reactive astrocytes surrounding triple-negative BrM in comparison to HER2-positive and luminal BrM, and these findings mirror those observed in animal models. A high STAT3 expression correlates with higher risk of intracranial recurrence and shorter progression-free survival, particularly in patients with triple-negative BrM.

Background: Glioblastoma (GBM) is a deadly brain cancer with a dismal prognosis. There is evidence that infiltration and therapy resistance in GBM are driven by tumor microtubes (TMs), ultra-long membrane-enclosed protrusions that serve as intercellular communication channels. The aims of this study were to investigate the role of TMs and identify the molecular drivers involved in TM formation.

Methods: We used patient-derived GBM neurosphere cultures that produce TMs to investigate TM dynamics, the proteins and pathways involved in TM formation, and the effect of targeting brain fatty acid-binding protein (FABP7) on mouse survival using an orthotopic model of GBM.

Results: The radial glial cell marker, FABP7, is highly expressed in TMs. Like GAP43, FABP7 is critically important for the formation of TMs in GBM neurosphere cultures. We show that GBM cells use TMs as a fiber network for rapid and directional migration. Our results indicate that GAP43 phosphorylation is required for TM formation, with GAP43 phosphorylation facilitated by FABP7 expression. We also show that depletion or inhibition of protein kinase C (PKC), the kinase responsible for GAP43 phosphorylation, decreases TM formation. Targeting FABP7 in an orthotopic mouse model of TM-forming GBM cells increases survival but does not sensitize tumors to radiation.

Conclusions: We found that the FABP7-PKC-pGAP43 axis is key to GBM TM formation, with TMs serving as networks for efficient long-distance cell migration. Our results indicate that TM formation can be mitigated by FABP7 inhibition with the potential of improving clinical outcomes in GBM patients.

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are rare, aggressive sarcomas, with 40% associated with neurofibromatosis type 1 (NF1). Surgical excision is the main treatment for localized disease; however, local recurrence (LR) remains high. Radiotherapy (RTx) is increasingly used to enhance local control in STS, but its use remains controversial due to the potential for increased major wound complications and an increased risk of secondary malignancies in NF1 patients. This study investigated the use and impact of RTx on local control in MPNSTs, particularly in the NF1 setting.

Methods: Surgically treated primary MPNSTs from 1988 to 2019 in the MONACO multicenter cohort were included. Differences in demographics, treatment, and RTx use between NF1 and non-NF1 cases were examined. Factors influencing RTx administration and LR were assessed via multivariable analyses.

Results: Among 499 patients (33.1% NF1), 143 (28.7%) experienced LRs. Radiotherapy was administered to 56.3% of patients (57.0% in the NF1 group), with 27.3% receiving neoadjuvant and 72.7% adjuvant RTx. RTx was administered significantly more often to high-grade and extremity tumors. While RTx did not affect overall survival, it reduced LR risk in sporadic cases (hazard ratio [HR] 0.530; 95% confidence interval [CI], 0.354-0.793) but not in the NF1 subgroup (HR 1.00; 95% CI, 0.545-1.85). In NF1 patients, a microscopically positive margin (R1) was the only risk factor for LR development (HR 2.1; 95% CI, 1.19-3.79).

Conclusions: RTx is frequently used in the treatment of MPNSTs, regardless of NF1 status. While it may affect the LR rate in sporadic cases, its impact on NF1 patients is less clear.