Neuro-oncology最新文献

Background: This study aimed to identify prognostic factors in patients with newly diagnosed primary central nervous system lymphoma (PCNSL) treated with high-dose methotrexate-based therapy and to develop a novel risk-stratification model using easily measurable clinical and laboratory parameters.

Methods: A total of 451 patients with newly diagnosed PCNSL were identified from a prospective registry at Asan Medical Center, Seoul. Patients were randomly assigned to a training cohort (n = 280; October 2002-August 2019) and an independent validation cohort (n = 171; September 2019-December 2023).

Results: With a median follow-up of 106.0 months (95% CI, 101.0-120.0), the median overall survival (OS) in the training cohort was 46.1 months (95% CI, 34.9-57.6). Independent predictors of worse OS (p < 0.05) included age ≥65 years, high serum β2-microglobulin levels (≥1.8 mg/L), elevated serum lactate dehydrogenase, and ECOG performance status >1. These four factors were combined to form the ABLE score, which stratified patients into low- (0 risk factors), intermediate- (1 risk factor), and high-risk (≥2 risk factors) groups. In the training cohort, median OS was 109.0, 49.0, and 18.0 months, respectively (p < 0.001). Validation in the independent cohort confirmed significant prognostic discrimination, with median OS of not reached, 53.1, and 19.0 months for each risk group (p < 0.001). Comparative analyses demonstrated that the ABLE model showed improved discrimination compared with existing systems. Bootstrap validation (n = 451) yielded an optimism-corrected C-index of 0.656 (95% CI, 0.628-0.685).

Conclusions: The ABLE risk-stratification model can effectively differentiate prognostic subgroups in patients with PCNSL.

Background: Oncolytic virotherapy holds promise for glioblastoma, but the intratumoral replication kinetics of oncolytic viruses and resistance mechanisms of tumor cells remain poorly understood, limiting the development of precise combinssation strategies to improve durable efficacy.

Methods: Using the translational RESCUE framework that synchronizes clinical trials with patient-derived xenograft (PDX) models, we profiled the replication kinetics of the oncolytic adenovirus YSCH-01 and performed genome-wide CRISPR activation screening to identify key genes restricting sustained viral replication. Through spatial transcriptomics combined with histological analyses, we delineated the spatial determinants that limit viral dissemination following oncolytic virus administration.

Results: We identified BCL10 as a key suppressor of sustained viral replication. Viral infection activated the BCL10-NF-κB pathway, triggering paracrine secretion of interleukin-8 (IL-8) from infected tumor cells. IL-8 induced senescence and fibrotic remodeling in neighboring uninfected cells, forming a previously unrecognized Tumor Self-Rampart (TSR)-a concentric barrier of senescent and fibrotic tumor cells that spatially confines viral propagation. TSR was validated in both PDX and patient tumors. IL-8 blockade with Reparixin or peri-dosing glucocorticoids effectively disrupted TSR formation, prolonged viral persistence, and enhanced therapeutic efficacy.

Conclusion: Glioblastoma mounts a spatial self-protective defense through IL-8-driven TSR formation that restricts oncolytic virus spread. IL-8 functions as both a pharmacodynamic biomarker and a therapeutic target, and its inhibition provides a rational strategy to overcome resistance and optimize GBM virotherapy.

Background: Meningioma is the most common primary CNS tumor, with high-grade cases exhibiting aggressive behavior, frequent recurrence, and poor prognosis. Currently, no systemic therapies are approved for recurrent or malignant meningiomas. Chimeric antigen receptor (CAR) T-cell therapy has shown efficacy in hematologic malignancies and promise for solid tumors, but its use for meningiomas has been underexplored. Mesothelin, a glycoprotein overexpressed in several solid tumors of mesodermal origin, may serve as a viable immunotherapeutic target. This study aimed to evaluate mesothelin as a CAR T-cell target in meningiomas.

Methods: Mesothelin expression was analyzed in patient-derived meningioma samples using immunohistochemistry, flow cytometry, and droplet digital PCR. Mesothelin-specific CAR T-cells were generated and evaluated invitro, exvivo using patient-derived organotypic tumor spheroids (PDOTS), and invivo using orthotopic meningioma mouse models of human xenografts. Cytotoxicity, T-cell proliferation, cytokine secretion, and tumor clearance were assessed.

Results: Mesothelin was detected in a subset of tumors across all meningioma grades at the transcript and protein levels, with surface expression confirmed in patient-derived primary cells. Mesothelin-specific CAR T-cells exhibited potent and specific cytotoxicity, T-cell activation, and cytokine secretion in vitro and effectively eliminated PDOTS. In orthotopic human xenograft models, mesothelin CAR T-cell therapy led to significant tumor regression and prolonged survival.

Conclusions: Mesothelin is a viable CAR T-cell target for meningiomas, and mesothelin-specific CAR T-cell therapy shows strong preclinical efficacy. These findings provide a rationale for early-phase clinical trials of mesothelin CAR T-cell therapy in patients with refractory meningiomas.

Background: Improved prognostic stratification, including imaging-based parameters, is needed to guide treatment decisions in IDH-mutant glioma.

Methods: In this bicentric retrospective study, 457 patients with IDH-mutant glioma and [18F]fluoroethyltyrosine or [11C]methionine positron emission tomography (PET) prior to radiotherapy or systemic treatment were included. Associations of maximum and mean tumor-to-background ratios (TBRmax/TBRmean) and PET-positive volume (PET volume) with time to next intervention (TTNI) and overall survival (OS) were analyzed.

Results: Overall, 251 (54.9%) patients with astrocytoma and 206 (45.1%) with oligodendroglioma were included. In patients with astrocytoma who underwent PET before resection, measurable disease according to PET RANO 1.0 criteria was associated with shorter TTNI compared to no/non-measurable disease (median 46.0 vs. 67.9 months; P = .004). Univariable analysis showed an association of TTNI with TBRmax, TBRmean, and PET volume in astrocytoma and PET volume in oligodendroglioma. Multivariable analyses including age, WHO grade, extent of resection, postoperative treatment, and magnetic resonance imaging (MRI)-based tumor extent indicated an association of TTNI with TBRmax (HR 1.48 [95%CI: 1.09-2.01]) and TBRmean (HR 1.93 [95%CI: 1.14-3.27]) in astrocytoma and PET volume (HR [10 ml increase]: 1.18 [95%CI: 1.03-1.36]) in oligodendroglioma. In astrocytoma, also OS was related to TBRmax (HR: 1.40 [95%CI: 1.13-1.74]), TBRmean (HR: 1.97 [95%CI: 1.21-3.22]), and PET volume (HR: 1.23 [95%CI: 1.10-1.37]) in univariable analysis. Further analyses considering timepoint of PET showed consistent results.

Conclusions: In this retrospective study, amino acid PET parameters were associated with outcome in newly diagnosed IDH-mutant glioma. Future clinical trials should include PET imaging to define imaging-based prognostic signatures.

Background: Preoperative embolization is hypothesized to reduce blood loss and operative time for meningioma resection, but the impact of preoperative embolization on long-term oncological outcomes and molecular features of meningiomas is incompletely understood. Here, we investigate how preoperative embolization influences perioperative and long-term outcomes as well as molecular features of atypical WHO grade 2 meningiomas.

Methods: Patients who underwent resection of WHO grade 2 meningiomas from 1997 to 2021 were retrospectively identified from an institutional database. Univariate and multivariate Cox proportional hazards modeling and propensity matching were used for clinical analyses. Available DNA methylation profiling, bulk RNA sequencing, and targeted gene expression profiling data were used to elucidate how preoperative embolization influences the molecular architecture of atypical WHO grade 2 meningiomas.

Results: A total of 319 patients with atypical WHO grade 2 meningiomas were identified, of which 106 (33.2%) underwent preoperative embolization without significant changes in perioperative outcomes, such as blood loss or operative time, in comparison to patients who did not undergo preoperative embolization. In propensity matched multivariate analyses, preoperative embolization was independently associated with longer recurrence-free survival (RFS, HR 0.55, 95% CI 0.31-0.96, P = .037), particularly in patients with subtotal resection (median RFS 16.2 years vs 5.9 years, P = .045; HR 0.32, 95% CI 0.14-0.70, P = .005). Bioinformatic analyses demonstrated that preoperative embolization led to enrichment of pathways linked to cellular differentiation and hypoxia, and suppression of pathways implicated in mitosis and cell cycle progression, suggesting that improved long-term oncological outcomes may occur through inhibition of the cell cycle in atypical WHO grade 2 meningiomas.

Conclusions: Preoperative embolization improves local control and modulates gene expression in atypical WHO grade 2 meningiomas, a subgroup of meningiomas that have intermediate clinical outcomes with standard interventions.

The alkylating agents temozolomide (TMZ) and lomustine (CCNU) are the most effective systemic agents for malignant gliomas. However, resistance-whether intrinsic or acquired-inevitably develops in all patients, and these tumors remain incurable. Although CCNU has demonstrated clinical benefit, its clinical use has been relatively limited due to a less favorable safety profile compared to TMZ. Recently, interest in CCNU and other nitrosoureas has been renewed in light of positive clinical trials in both adult and pediatric gliomas. Despite this renewed attention, critical questions remain unaddressed regarding the use of nitrosoureas. While resistance and response to temozolomide have been associated with the status of both MGMT and the mismatch repair DNA repair pathway, our understanding of the unique mechanisms of resistance to nitrosoureas beyond MGMT remains limited. Recent advances in molecular biology, preclinical models, and the use of longitudinal analyses of treated samples provide new insights, offering opportunities to refine clinical use and develop novel strategies. In this review, we explore the current role of nitrosoureas in glioma treatment, examine known and emerging mechanisms of sensitivity and resistance to these agents, and explore the potential for combination approaches to enhance their efficacy.

Background: Leptomeningeal disease (LMD) from solid tumors has a dismal prognosis, even following treatment with anti-PD-1 therapy. We performed a phase IB study evaluating the safety of Avelumab with whole brain radiotherapy (WBRT) in LMD (NCT03719768).

Methods: Fifteen patients were enrolled with LMD from breast, lung, nasopharyngeal, ovarian, and pancreatic tumors. Patients were treated with Avelumab with WBRT, with the first infusion of Avelumab starting 14 days pre-WBRT and continuing during and post-WBRT for up to 5 cycles. Primary endpoints were safety and 3-month OS (OS3). Secondary endpoints included assessment of immune cells in the cerebrospinal fluid (CSF) using single-cell RNA-sequencing (scRNA-Seq) pre- and post-last treatment of Avelumab.

Results: DLTs occurred in 2 patients, ie, adrenal insufficiency, hypothyroidism, and pneumonitis. Treatment-related toxicities occurred in 5 patients with grade 1/2 and 5 patients with grade 3/4. Immune-related adverse events occurred in 5 patients with grade 1/2 and 3 patients with grade 3/4. The OS3 was 67% (10 of the 15; 95% CI: 38%-84%). Median-OS was 3.85 months (95% CI: 0.9-34.4 months) and median-PFS was 3.85 months (95% CI: 0.9-12.1 months). scRNA-Seq analysis of CSF pre- and post-last-treatment showed Avelumab + WBRT stimulated an adaptive immune response associated with a decrease in regulatory T cells (Tregs), among other changes in the expression of immune checkpoints on CD8 + T cells and macrophages.

Conclusions: The combination of Avelumab and WBRT is safe and demonstrates activity in patients with LMD. The identification of high levels of Tregs and macrophages in the CSF of LMD patients offers future avenues for therapeutic development.