Neuro-oncology advances最新文献

Background: Lysine-specific demethylase 1 (LSD1) is overexpressed in glioblastoma, contributing to tumor growth and treatment resistance. LSD1 inhibitors have shown preclinical promise but have had limited clinical development for glioblastoma. Given the frequent kinase pathway alterations seen in glioblastoma, the interplay between LSD1 inhibition and kinase signaling pathways was investigated.

Methods: Glioblastoma stem cell (GSC) lines and normal human astrocytes (NHAs) were treated with catalytic LSD1 inhibitors, NCD38 and bomedemstat, and the LSD1 scaffolding inhibitor, seclidemstat alone and in combination with kinase inhibitors, including osimertinib, afatinib, and ulixertinib. The effect on cell viability, proliferation, and neurosphere formation was assessed, and synergy scores were calculated using Bliss synergy models. Kinase signaling was analyzed and in vivo efficacy was evaluated in orthotopic xenograft models.

Results: LSD1 knockdown and seclidemstat reduced kinase signaling, while catalytic LSD1 inhibitors increased kinase activity or had no effect. Catalytic LSD1 inhibitors combined with kinase inhibitors, synergistically reduced GSC viability and proliferation while sparing NHAs. Combination treatment consistently reduced phospho-S6 ribosomal protein levels in three different GSC lines, and basal phospho-S6 ribosomal protein levels across the GSCs and the NHAs were negatively correlated with a synergistic response. The generation of an NCD38-resistant GSC showed increased kinase activity and was associated with enhanced osimertinib sensitivity. Combined treatment with NCD38 and osimertinib in glioblastoma-bearing mice delayed tumor growth and improved survival outcomes.

Discussion: These findings provide a rationale for further investigation of combination therapies of catalytic inhibitors of LSD1 and EGFR and dual-targeted inhibitors to overcome resistance and improve outcomes.

Abstract: BackgroundGlioblastoma (GBM) is an aggressive brain tumor. The authors of this study wanted to find out whether areas of reduced blood flow, called ischemia, that appear after surgery affect how long people live with this disease. To do this, they reviewed scans from 451 patients taken within three days after tumor removal and measured the size of any new areas with poor blood supply. Their results showed that larger areas of ischemia were linked to shorter survival. The prognostic relevance of postoperative ischemia in GBM remains unclear. This study investigated the association between infarct volume and survival in patients with Isocitrate Dehydrogenase (IDH)-wildtype GBM.

Methods: We retrospectively reviewed 451 patients with IDH-wildtype GBM who underwent resection between 2013 and 2024 and had diffusion-weighted imaging within 72 h postoperatively. Ischemic changes were defined as new areas of diffusion restriction and stratified into none/rim-only, small (<5 cm³), and large (≥5 cm³) infarcts. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier and Cox regression models adjusted for age, preoperative KPS, tumor size, extent of resection, MGMT status, adjuvant therapy, and postoperative deficits.

Results: Large infarcts were associated with shorter median PFS (7.0 months [95% CI: 5-9]) and OS (14.0 months [95% CI: 9-18]) compared to small infarcts and none/rim-only (PFS: P = .07; OS: P = .001). In multivariable models, infarct volume was independently associated with reduced OS (per cubic centimeter increase, HR = 1.02, 95% CI: 1.01-1.032; P = .003), while its association with PFS did not reach statistical significance (HR = 1.01, 95% CI: 1.0-1.02; P = .13). When modeled categorically, large infarcts remained predictive of shorter PFS (HR = 1.4, 95% CI: 1.01-1.9; P = .04) and OS (HR = 1.7, 95% CI: 1.2-2.4; P = .001).

Conclusions: Infarct volume is independently associated with survival in IDH-wildtype GBM. These findings highlight the clinical relevance of postoperative ischemia and may point toward ischemia-related mechanisms as targets for future therapeutic investigation.

Background: The impact of systemic therapy (ST) on outcomes for patients with brain-only metastases (BrM) in the absence of extracranial disease (ECD) is not well established. We compared outcomes between patients with BrM treated with stereotactic radiosurgery (SRS) who received ST ≤3 months (mos), >3 mos, or not at all after SRS.

Methods: We identified BrM patients who completed SRS across two institutions from 1/2015 to 12/2020. Intracranial progression after SRS was determined by brain MRI radiographic recurrence. Overall survival (OS) and intracranial progression free survival (iPFS) estimates were also generated.

Results: In total, 342 patients with BrM were identified. Primary sites included lung (73%), breast (12%), and additional sites (15%). Almost half, 169 (49%), received no ST, 80 (23%) received ST ≤3 mos, and 93 (27%) received ST >3 mos after SRS. Median age was younger in the ST >3 mos cohort (60.5years) compared with ST <3mo (67.7years) and no ST (67.0years), P = .0002. Median OS differed significantly between groups: ST ≤3 mos with 24.9mos (95%CI: 16.6-51.1), ST >3 mos with 27.5mos (95% CI: 20.6-37.5), and no ST with 11.0mos (95%CI: 9-17.5), P = .002. Median iPFS differed significantly between groups: ST ≤3 mos 16.1mos (95% CI: 9.5-33.7), ST >3 mos 8.9mos (95% CI: 6.9-13.5), and no ST 10.0mos (95% CI: 6.7- 15.1). However, timing of ST was not significant multivariate analysis.

Conclusions: In our cohort of BrM patients, ST after SRS improves OS regardless of timing. ST ≤3 mos may improve iPFS compared with ST >3 mos after SRS, which warrants further investigation. Appropriate patients with BrM should be referred for a multi-disciplinary discussion of ST following SRS.

Background: Brain metastasis is the most ominous form of cancer relapse. There is urgent need to develop preclinical mouse models to study brain metastasis and new therapeutic strategies. Patient derived xenograft (PDX) models are clinically relevant mouse models. The brain stromal cells play critical roles on metastatic initiation and outgrowth. We have shown that PPARγ signaling in cancer cells is activated by astrocytes to increase brain metastatic outgrowth. Here, we aim to compare ectopic and orthotopic brain metastasis PDX models to address whether the unique brain microenvironment affects therapeutic efficacy of PPARγ antagonist.

Methods: A collection of surgically resected brain metastasis tissues from cancer patients were used to generate PDX models. Ectopic and orthotopic brain metastasis PDX models were generated and characterized. The tumor growth was tracked in both PDX models when treated with PPARγ antagonist.

Results: The growth rate of PDX tumors increased over passages in our ectopic PDX models and maintains in the orthotopic PDX models. Brain stromal cells were absent in the ectopic PDX tumors. Brain metastasis cancer cells sustained the PPARγ expression in both ectopic and orthotopic PDX tumors, at the similar level as the original brain metastasis tissues. However, PPARγ antagonist only decreased tumor growth in the brain without affecting subcutaneous tumors.

Conclusions: Our results show that PDX models are successfully generated from clinical brain metastasis tissues and maintain the molecular characteristics in the brain metastasis cancer cells. Moreover, our study indicates the importance of the brain microenvironment to the therapeutic response in brain metastasis.

Background: Glioblastoma (GBM) lacks effective therapies for recurrent disease. Unlike cancers with successful fusion-targeted treatments (eg BCR-ABL1 in CML), the incidence and therapeutic potential of gene fusions in GBM remain unclear. We analyzed a large genomic database to define fusion frequency and molecular associations.

Methods: 4800 IDH-wildtype GBM samples (WHO 2021) underwent NextGen DNA sequencing (592-gene panel/whole exome) and Whole Transcriptome Sequencing for fusions at Caris Life Sciences. Fisher-Exact/Chi-Square tests, adjusted by Benjamini-Hochberg (q < 0.05), assessed significance.

Results: Pathogenic fusions occurred in 428 (8.9%) samples, primarily FGFR3 (37%, n = 159; FGFR3: TACC3, n = 134), MET (21%, n = 92), and EGFR (20%, n = 87). Pathogenic or likely pathogenic fusions included NTRK2 (n = 27), PDGFRA (n = 23), ROS1 (n = 14), and BRAF (n = 10). Fusion-positive tumors had higher MET (7.5% vs. 0.7%), FGFR3 (5% vs. 0.2%), CDK4 (17% vs. 11%), and MDM2 (12% vs. 7.5%) amplifications, but lower EGFR mutations (6.1% vs. 18%), amplifications (6.1% vs. 18%), and EGFRvIII (11.9% vs. 22.5%) (all q < 0.05). Median survival was 16.6 months (fusion-positive) vs. 15.5 months (fusion-negative) (P = 0.043). Tyrosine kinase inhibitor (TKI)-treated fusion-positive patients (n = 37) showed no significant survival benefit (18.4 vs. 16.5 months, P = .971).

Conclusions: Approximately 9% of GBMs harbor targetable fusions, with five genes (FGFR3, MET, EGFR, NTRK2, PDGFRA) comprising 8%. These findings support multi-arm clinical trials to evaluate targeted therapies, potentially improving outcomes for molecularly defined GBM subgroups.

Abstract: BackgroundDespite intensive therapies, outcomes for high-risk pediatric brain tumors (PBTs) remain dismal, prompting the search for novel treatments. DNA methyltransferase inhibitors (DNMTi) have been shown to prime tumors to improve response to checkpoint inhibition. The aim of this study was to investigate the potential of decitabine (DAC), in combination with a PD-1 inhibitor, to improve survival in pediatric high-risk brain tumor models.

Methods: Analysis of human PBT datasets was performed to determine gene expression levels of immune cell markers. Tumor response to DAC, with or without a PD-1 inhibitor, was tested in murine models representing H3-wildtype diffuse intrinsic pontine glioma (DIPG), H3K27-mutant diffuse midline glioma (DMG), atypical teratoid rhabdoid tumor (ATRT), and medulloblastoma (MB). CyTOF analysis of allograft tumors was performed to characterize changes within the tumor microenvironment.

Results: Analysis of PBT subtypes revealed heterogeneous expression of immune cell markers, checkpoint receptors, and MHC molecules. DAC treatment decreased DNA methylation and increased neoantigen expression in human and mouse tumor cells. DAC treatment resulted in prolonged survival in syngeneic mouse models of DIPG and ATRT but not DMG and MB models. However, no added survival benefit was observed when combined with a PD-1 inhibitor. CyTOF analysis of mouse tumors revealed changes in local immune cell infiltration.

Conclusions: DAC alone or in combination with a checkpoint inhibitor can alter the immune microenvironment in mouse tumor models. Changes were observed in H3-wildtype DIPG and ATRT models, suggesting that certain tumor subtypes may respond to immune priming with DNMTi.

Abstract: BackgroundSeizures are a common and disabling symptom of adult-type diffuse gliomas, affecting quality of life and potentially influencing tumor progression. Despite their clinical significance, seizure outcomes are often underreported or heterogeneously measured in clinical trials.

Objective: To assess how seizure outcomes are reported in clinical trials for adult-type diffuse glioma.

Methods: We systematically reviewed glioma clinical trials initiated after January 1, 2010, through June 16, 2025, on ClinicalTrials.gov that included seizure-related outcomes. Each trial was manually screened to characterize how seizures were defined, measured, and categorized.

Results: Of 2,801 clinical trials identified, 65 (2.3%) included seizure-related outcomes. Among these, 20 designated seizures as a primary outcome, though many grouped them within broader safety endpoints. Seizures were often listed as secondary outcomes (n = 23), adverse events (n = 11), or within quality-of-life assessments (n = 8). Reporting was highly variable; many trials used binary metrics. As few as 9 trials systematically assessed seizures using International League Against Epilepsy (ILAE) guidelines for seizure tracking (eg seizure diaries or structured EEG evaluation), and only 7 reported outcomes with standardized scales such as the ILAE outcome classification or the Engel classification, with rare use of newer tools such as the Seizure Control Composite Index.

Conclusions: Despite their clinical significance, seizure outcomes are rarely and heterogeneously reported in clinical trials for adult-type diffuse gliomas. Incorporating standardized, seizure-specific endpoints may better align glioma research with patient-centered and disease-specific outcomes.

Background: Desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA) is a rare, low-grade tumor of infants. They are usually composed of a mixed astrocytic and neuronal component with desmoplastic stroma and embryonal-looking areas. Despite some recent reports, clinical, morphological and molecular features of DIG/DIAs are still not well characterized. Here, we present a series of 8 DIG/DIA cases.

Methods: Hacettepe University and Koc University Hospital, Departments of Pathology, databases were screened for DIG/DIA. Eight patients were identified. All the slides were reevaluated, and patients' clinical data were obtained. All cases were tested for BRAF V600 mutation and 3 BRAF V600 wild-type cases were sequenced.

Results: Median age at the diagnosis was 5.5 months (4-30 months). The female to male ratio was 6:2. Two cases recurred. Four cases showed BRAF p. V600 mutation. Of those BRAF p. V600 wild-type cases, one harbored TMEM106B::BRAF fusion, described for the first time in a DIG/DIA case.

Conclusions: DIG/DIA is a low-grade tumor seen in early childhood and characterized by an indolent clinical course. The most common molecular signature of these tumors is BRAF alterations, including rearrangements. The primary differential diagnosis is infant-type hemispheric glioma and given the similarities, pathologists must remain careful to ensure accurate diagnosis.

Background: With less than 650 published cases, combination tumors of the nervous system, that is, two locally intertwined but histologically distinct tumor entities, pose a rare constellation, its clinical relevance still being a matter of debate.

Methods: A consecutive cohort of 2530 patients operated on meningioma or hemangioblastoma between 2009 and 2021 was retrospectively screened for concomitant neoplastic disease to identify cases of combination tumors. Additionally, all available literature published between 1930 and 2021 was compiled in a comprehensive review.

Results: Our cohort comprised 144 cases of patients with concomitant neoplastic disease and among those 10 instances of combination tumors. Another instance occurred after our screening period. Benign entities were meningiomas, but no hemangioblastoma. Contributing tumors were adenocarcinomas, lymphoma, glioblastoma, pituitary neuroendocrine tumors, and neurinoma. Patients' age ranged from 41 to 81 years with a slight preference for females. Identification of concomitant neoplasia was first achieved due to the combination tumor in about half of our cases. For the rest, median latency until manifestation of the combination tumor was 9 years. The odds ratio for a combination tumor was 17.6 for meningioma patients with known concomitant neoplasia, but it was preoperatively suspected in 18.2% of cases only.

Conclusion: Presenting one of the largest clinical series, we provide evidence that known concomitant neoplasia in patients with suspected meningioma should make clinicians consider a combination tumor. Confirmation may lead to therapeutic consequences, largely contributing to long-term prognosis. Furthermore, we present the most extensive literature review on the matter to date.