Neuro-oncology最新文献

Background: Intracranial solitary fibrous tumors (SFTs) are rare, aggressive neoplasms with high local recurrence. This study evaluates the efficacy and prognostic factors of single-fraction stereotactic radiosurgery (SRS).

Methods: This multicenter retrospective study included 107 patients (253 SFTs) treated with single-fraction SRS at 18 centers (1989-2024). We analyzed local control (LC), intracranial tumor control (ITC), overall tumor control (OTC), progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS). Cox regression identified prognostic factors.

Results: Median follow-up was 33 months. LC was 68.4% (5-yr: 56.8% and 10-yr: 38.8%). ITC 54.2% (5-yr: 48.5%) and OTC 50.5% (5-yr: 44.0%). PFS was 56.3% and 30.2% at 5 and 10 years, respectively. DSS remained high at 89.7% (5-yr) and 79.7% (10-yr), while OS was 79.3% (5-yr) and 55.2% (10-yr). Independent predictors of LC included recurrent vs. metastatic SFTs (HR: 1.96, p = 0.028), margin dose ≤16 Gy (HR: 2.35, p = 0.006), larger tumor volume (HR: 1.05, p < 0.001), and longer diagnosis-to-SRS duration (HR : 1.02, p < 0.001). Older age (HR: 1.03, p = 0.014) and longer resection-to-SRS duration (HR: 1.02, p = 0.018) predicted worse ITC. Age significantly affected OS (HR: 1.06, p < 0.001) and PFS (HR: 1.03, p = 0.037). Longer diagnosis-to-SRS (HR: 1.03, p = 0.002) and resection-to-SRS durations (HR : 1.02, p = 0.030) predicted worse PFS. KPS score >70 predicted better outcomes across ITC, OTC, DSS and OS. Radiation-related adverse effects occured in 2.8%.

Conclusion: SRS offers reasonable tumor control and favorable long-term survival in the adjuvant and salvage setting for patients with residual, recurrent, or metastatic intracranial SFTs. Key prognostic factors included tumor volume, recurrence status, and timing of SRS.

Background: Lower grade gliomas (LGGs) typically affect younger adults and are associated with long-term survival. Treatment-related toxicities, especially neurocognitive and neuroendocrine effects, are a concern. Proton therapy may reduce these risks by minimizing radiation exposure to healthy brain tissue. This study evaluates the safety and efficacy of proton therapy in LGG patients, focusing on neurocognitive, neuroendocrine, and quality-of-life (QOL) outcomes.

Methods: This single-institution, prospective phase 2 trial enrolled 60 patients with WHO grade 1-2 gliomas or IDH-mutant grade 3 gliomas. Proton therapy was delivered at 54 Gy(RBE) or 59.4 Gy(RBE) by tumor grade. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), neurocognitive and neuroendocrine function, and QOL. Neurocognitive testing occurred at baseline and biennially. QOL was assessed using the FACT-Brain questionnaire. Toxicities were graded per CTCAE v4.0.

Results: With a median follow-up of 7.0 years, 5-year PFS and OS were 79.1% and 85.6%, respectively. PFS was highest in IDH-mutant, 1p/19q co-deleted gliomas (100%) and lowest in IDH-wildtype tumors (62.5%). New neurocognitive deficits occurred in 26% of patients at 5 years. Neuroendocrine dysfunction occurred in 5.3%, with only one case attributed to radiation. QOL declined transiently at 6 months, with 15% showing clinically meaningful decline at 5 years. No late grade 3 toxicities were observed; one case of grade 4 radionecrosis occurred.

Conclusions: Proton therapy for LGG can offer effective disease control with modest long-term toxicity. These findings support its use as a standard radiation modality and highlight the need for comparative trials with photon therapy.

Background: The brain is a common site of relapse in inflammatory breast cancer (IBC), an E-cadherin-positive, aggressive form of breast cancer. Elevated serum levels of soluble E-cadherin (sEcad), an 80-kDa fragment, correlated with poorer outcomes and increased brain metastases in patients with metastatic IBC. We hypothesize that sEcad is a driver of brain metastasis in IBC.

Methods: Serum sEcad levels from 348 IBC patients were quantified by ELISA. To examine sEcad function, we used recombinant sEcad protein and generated stable IBC cell lines by cloning and overexpressing Flag-tagged sEcad. Control and sEcad-overexpressing MDA-IBC3 and SUM149 cells were injected into SCID/Beige mice to evaluate brain metastasis burden and survival, and a brain-permeable CXCR2 inhibitor was also tested for efficacy in these models.

Results: Higher serum sEcad levels correlated with poorer overall survival, earlier metastasis, and increased brain metastasis. In vitro, recombinant sEcad and stable sEcad overexpression in IBC cell lines promoted invasion, resistance to anoikis, and activation of pro-survival NF-κβ signaling. In vivo, mice injected with sEcad-overexpressing IBC cells had increased metastatic burden and reduced overall and brain metastasis-free survival. Further, sEcad induced reactive astrocytosis through the CXCL1/CXCL8-CXCR2 axis, and treatment with a brain-permeable CXCR2 antagonist reduced metastatic burden and prolonged survival in the brain metastasis models.

Conclusion: sEcad drives brain metastasis by promoting invasion and anoikis resistance in cancer cells and inducing an inflammatory brain microenvironment via a targetable CXCL1/CXCL8-CXCR2 axis. These findings uncover a novel and critical role for sEcad and highlight CXCR2 as a therapeutic target in patients with metastatic IBC.

Background: Intracranial mesenchymal tumors, FET::CREB fusion-positive (ICMT), show fusions involving FET RNA-binding protein family genes (EWSR1 or FUS) and CREB family of transcription factors (ATF1, CREB1 or CREM). The methylation signature(s), gene expression characteristics and clinical behavior of this important tumor type require further characterization.

Methods: We study the methylation profiles of 81 ICMT cases (61 newly profiled cases and 20 cases from publicly available sources). Clinicopathologic and genomic data were recorded for each case when available.

Results: ICMT showed a relatively distinct methylation signature compared to related tumors. Among the 65 cases where fusion types were documented, the identified fusions included EWSR1::ATF1 (25 cases), EWSR1::CREB1 (12 cases), EWSR1::CREM (21 cases), FUS::CREM (3 cases) and SMARCA2::CREM (4 cases). We confirmed the prior description of two distinct subgroups of ICMT (subclasses A and B). The majority of the cases belonged to subclass A (n = 69; 85%), which showed higher median age compared to subclass B patients (26 years vs. 15 years). Subclass B cases (n = 12; 15%) showed shorter progression-free survival (p < 0.01). Gene expression analysis of ICMT showed key overexpressed markers in ICMT, with significant CREM overexpression regardless of fusion type, when compared to either meningioma alone, or a larger group of CNS tumors.

Conclusions: This work provides further characterization of ICMT as an important CNS mesenchymal neoplasm that is prone to tumor recurrence, showing 2 prognostically relevant methylation subclasses, and warranting diagnostic distinction from other epigenetically and histologically related tumors. ICMTs show substantial overexpression of the CREM gene, independent of fusion type.

Background: High-grade meningiomas (HGMs) recurring after X-ray treatment show poor prognosis. We assessed the effectiveness and safety of boron neutron capture therapy (BNCT) in patients with refractory recurrent HGMs.

Methods: This phase II investigator-led randomized controlled trial utilized an accelerator-based BNCT system to treat refractory recurrent HGMs. Patients were randomly assigned in a 2:1 ratio to the BNCT (12 patients) and control (6 patients) arms. Progression-free survival (PFS) judged by an independent third-party committee was the primary endpoint and PFS judged by the investigators and overall survival of the BNCT arm were the secondary endpoints. The control arm received rescue BNCT if they show disease progression.

Results: Three and two patients with World Health Organization (WHO) grade 3 disease were assigned to the BNCT and control arms, respectively; the remaining patients had WHO grade 2 disease. Median PFS (primary endpoint) was 14.4 months (95% confidence interval (CI): 7.9-26.4) in the BNCT arm and 1.4 months (95% CI: 1.0-9.0) in the control arm. Median PFS (secondary endpoint) was 14.7 months (95% CI: 7.6-22.8) in the BNCT arm and 1.5 months (95% CI: 1.0-9.0) in the control arm. The differences were statistically significant (log-rank test, P = 0.0157 and P = 0.0002, respectively). Five patients in the control arm received rescue BNCT. The objective response rate in the BNCT arm was 27.3%.

Conclusions: BNCT is an effective treatment for refractory recurrent HMGs. Compared with conventional therapy, PFS in both primary and secondary endpoints were considerably improved.

Background: High-dose methotrexate (MTX)-based chemotherapy is the mainstay of treatment of primary central nervous system lymphoma (PCNSL). Only ∼60% of patients achieve a complete response to first line therapy with frequent relapses. The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has shown promising antitumor activity in recurrent/refractory PCNSL. Methods: The goal of the current single-center phase 2 trial was to explore whether the addition of ibrutinib to the combination of rituximab, methotrexate, procarbazine, and vincristine ((R-MVP/i) increases complete response rate (CCR).

Results: Thirty newly diagnosed PCNSLs were enrolled; median age 69 (range 41-79), median ECOG = 1. 29 patients completed R-MVP/i, 1 withdrew consent after 2 cycles.A CR/CRu was achieved in 29 patients and a partial response in 1 for a CRR of 29/30 (97%, 95% CI : 83.3%, 99.8%)). Treatment was well tolerated with no grade 5 toxicity was observed. Eight patients experienced 13 grade 4 toxicities (lymphopenia (n = 3), neutropenia (n = 4), thrombocytopenia (n = 3) white cell count decrease (n = 3)). The most common toxicities were thrombocytopenia, anemia, lymphopenia and liver enzyme elevations. No Aspergillus or Pneumocystis infections occurred. No refractory disease was observed. For the 29 patients completing the trial, 19 received consolidation with cytarabine (Ara-C), 8 autologous stem cell transplant, 1 rituximab maintenance and 1 was observed without maintenance or consolidation. At a median follow up of 25.1 months (range 3.3-49.2), the median progression-free (PFS) and overall survival (OS) was not reached with a 2-year PFS of 84.2% (95% CI: 62.7%-93.9%).

Conclusions: R-MVP/i was well tolerated and associated with excellent disease control and survival.

Background: IDH1R132H is the defining mutation of low-grade gliomas (LGGs), inflicting broad epigenetic rewiring that leads to malignant transformation. Recent studies demonstrated that cell fate change from astrocyte to LGG is accompanied by redistribution of H3K4 methylation. By modulating H3K4-methyltransferase KMT2A in a conditionally IDH1R132H-expressing human astrocyte model system, we sought to define requirements of IDH1R132H dependent gliomagenesis and identify novel therapeutic targets.

Methods: Using KMT2A inhibitor MM-102, we targeted H3K4me3 in IDH1R132H -expressing astrocytes, profiling L1CAM expression, proliferation, clonogenicity, invasion and migration, transcriptional and translational changes. Findings were validated in patient-derived IDH1R132H glioma lines with shRNA-mediated knockdown. Epigenetic transformation was characterized with CUT&Tag and MethylationEPIC. Downstream targets were assessed utilizing siRNAs.

Results: KMT2A inhibition significantly decreased L1CAM expression and led to broad transcriptional downregulation, including LGG marker genes. Analyses of transcriptomics and proteomics pointed to altered lipid metabolism and migratory capacity. Phenotypic characterization showed impaired invasion, migration and proliferation. We observed significantly reduced deposition of H3K4me3 at promoters of DEGs and enhanced global DNA methylation. We identified SCD as putative KMT2A-dependent effector whose knockdown reduced clonogenicity. In patient-derived models, KMT2A suppression impaired viability and spheroid growth in vitro; however, in an orthotopic TS603 model, knockdown shortened survival, indicating stage- and context-dependent effects.

Conclusions: Disrupting KMT2A-mediated H3K4me3 reshapes the epigenome and attenuates LGG-relevant programs and phenotypes in vitro, supporting a strong role in tumor initiation. In vivo, the TS603 survival result highlights context-dependent maintenance and motivates cautious, microenvironment-aware therapeutic exploration of the KMT2A axis and downstream targets such as SCD.

Background: The prognosis of patients with recurrent WHO grade 4 glioma is poor, particularly in glioblastoma (GBM), which has a median survival of approximately 6 months and no effective treatment options. We evaluated the short-term (28-day) safety and efficacy of ON-01, an engineered recombinant oncolytic herpes simplex virus type-1, in patients with recurrent WHO grade 4 glioma.

Methods: In this single-arm, phase 1/2 clinical trial, eligible patients received intratumoral injections of ON-01 under stereotactic guidance. The primary endpoint was to assess the short-term safety profile of ON-01 treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the 2-year OS rate. An exploratory objective was to identify tumor-related biomarkers predictive of treatment efficacy.

Results: Of the 30 patients treated with ON-01, 13 (43.3%) were male, and the median age was 50.0 years (range, 22-75). A total of 36 grade 1, 12 grade 2, and 2 grade 3 adverse events were reported. Among all treated patients, the median OS was 12.0 months (95% CI, 10.1-13.9), median PFS was 3.0 months (95% CI, 1.7-4.3), and 2-year OS rate was 27.7% (95% CI, 12.6%-45.0%). Seven patients with recurrent multifocal gliomas demonstrated regression of non-injection site lesions following ON-01 therapy. Furthermore, patients with elevated expression of herpesvirus entry mediator exhibited significantly prolonged survival (p=0.015).

Conclusions: Intratumoral infusion of ON-01 appeared safe and demonstrated efficacy in patients with recurrent malignant glioma, with no evidence of neurotoxicity. The therapeutic response to ON-01 may be associated with HVEM expression levels.