Neuro-oncology最新文献

Background: The life expectancy of patients with diffuse IDH-mutant low-grade gliomas (IDHmt LGG) ranges from 5 to over 20 years. Tumor behavior, including spontaneous growth rate, varies even within homogeneously classified subtypes of oligodendroglioma and astrocytoma. Risk-adjusted treatment strategies are needed to avoid therapy-related toxicities, without compromising outcome. The spontaneous tumor volume growth rate (TVGR) serves as a prognostic marker and predicts response to therapy. Accurate prediction of TVGR through biomarkers would enable an improved evidence-based risk management.

Patients & methods: A cohort of 77 patients treated in Montpellier, France, for IDHmt LGG grade II (WHO 2016) (29 oligodendrogliomas, 48 astrocytomas) was constituted (age >18 years; MRI scans, frozen tumor tissue). The DNA methylome (Illumina, EPIC array) and transcriptome (RNAseq) were established. TVGR was determined based on serial MRIs collected over the "watch & wait" period before first treatment beyond surgery. Transcriptomic and methylome data were analyzed for signatures associated with TVGR using rank-rank regression followed by preranked gene set enrichment analysis.

Results: : The median TVGR was lower in IDHmt codeleted compared to non-codeleted LGG, (0.241 year-1 range 0.082-0.366 vs 0.424 year-1 range 0.264-0.609, p < 0.001). In codeleted IDHmt LGG, TVGR was associated with upregulated gene signatures for neuronal systems, synaptic activity, and activation of repressed or poised signatures of neural progenitor cells; while the TVGR in non-codeleted IDHmt LGG was dominanted by upregulated proliferation-related signatures, including DNA replication and repair.

Conclusion: Spontaneous TVGR of codeleted and non-codeleted IDHmt LGG involve distinct biological processes, suggesting possible differences in response to therapies.

Background: Poly ADP-ribose polymerase-1 (PARP1) is a key enzyme in DNA damage repair and an established target for cancer drug treatment. Although the emergence of non-invasive imaging of PARP using PET has opened new opportunities in cancer diagnosis and drug development, subtype selective imaging of the enzyme, and particularly in brain, remains an unmet need.

Methods: The potent and selective novel PARP inhibitor AZ14193391 was labeled with carbon-11 and evaluated as a candidate PET radioligand for PARP1 through a series of translational in vitro and in vivo molecular imaging studies. These studies encompassed PET in non-human primates, healthy volunteers and patients with glioblastoma.

Results: Robust radioligand binding to PARP1 was observed in the healthy non-human primate and human brain both in vitro and in vivo. Elevated tumor binding with high contrast was also demonstrated in patients with glioblastoma.

Conclusions: The novel PET radioligand, [11C]AZ14193391 enables subtype selective imaging of PARP1 binding. Its ability to image this protein in the human brain paves the way for accelerated research, diagnosis and drug development in neuro-oncology.

Background: Astroblastomas are rare brain tumors predominantly affecting children and young adults, for which molecular subtypes and clinical management remain undefined.

Methods: We analyzed tumor samples, molecular profiles, and clinical data from 200 patients, classified as "Astroblastoma, MN1-altered" under WHO criteria, using DNA methylation profiling, DNA/RNA profiling/sequencing, and survival analyses.

Results: DNA methylation analyses identified three groups: Group A (n = 143, characterized by MN1::BEND2 fusions, predominantly supratentorial location, with striking female predominance and favorable survival); Group B (n = 37, epigenetically and transcriptionally closely related to Group A, but characterized by EWSR1::BEND2 fusions, with spinal and infratentorial locations and poor prognosis); and Group C (n = 20, epigenetically and transcriptionally distinct, characterized by MN1::CXXC5 fusions, exclusively supratentorially located, with favorable survival). Progression-free and overall survival were significantly shorter in Group B (5-year PFS 14%; 10-year OS 54%) compared to A (5-year PFS 47%; 10-year OS 89%) and C (5-year PFS 75%; 10-year OS 89%). Radiotherapy improved PFS in Group B (hazard ratio 0.25), while no clear benefit was identified for Group A and C.

Conclusions: Astroblastoma, MN1-altered, comprises three molecularly and clinically distinct groups, characterized by different fusion genes, including those without MN1. These new insights, including identification of potential predictive biomarkers like 14q/16q loss, provide a framework for development of risk-stratified therapeutic approaches. Importantly, we identified a molecularly defined high-risk group that benefits from radiation therapy. Our findings redefine Astroblastoma as a molecularly diverse tumor type, propose a refined classification, support the development of risk-adapted therapeutic strategies and provide a rational standard of care.

Background: The utility of chemotherapy for childhood ependymoma is uncertain without a prior randomized trial.

Methods: ACNS0831, a multi-center phase 3 randomized study conducted through the Children's Oncology Group (COG), included patients 1-21 years with newly diagnosed intracranial ependymoma. Patients with complete/near total resections (GTR/NTR) or complete response (CR) to induction therapy were randomized to radiation (RT) alone or RT followed by chemotherapy (RT-CHEMO). Primary outcomes were event free survival (EFS) and overall survival (OS). Due to anticipated non-compliance with chemotherapy, an 'as treated' analysis was planned. Patients with sub-total resection (STR) were non-randomly assigned to RT-CHEMO. Grade 2 supratentorial tumors, GTR or CR to induction therapy were observed.

Results: Of 449 eligible patients, 325 with GTR/NTR or CR were randomized. Five-year EFS was 63.7% (95% CI 55.1-71.1%) for RT only (n = 161) versus 69.2% (60.8-76.3%) for RT-CHEMO (n = 164) (one-sided log-rank p = 0.299, HR = 0.866). Five-year OS was 86.9% (79.8-91.6%) for RT only versus 88.3% (81.8-92.6%) for RT-CHEMO (one-sided log-rank p-value = 0.172, HR = 0.757). The 'as treated' and 'as randomized' analysis results were similar. Sixty-three subjects with STR were assigned to RT-CHEMO; 5-year EFS was 33.6% (22·1-45·5%) and OS 74.0% (60.5-83.5%). Supratentorial grade 2 tumors with GTR or CR were observed with a 5-year EFS of 66.9% (49.0-79.7%) and OS of 100%. Molecular classification was provided for 94% (n = 422) of all subjects.

Conclusions: Primary analysis showed no benefit for maintenance chemotherapy. Further follow-up is important to assess its effect on late relapses. This is the largest cohort of molecularly classified ependymomas treated on a Phase 3 randomized trial.

Background: To determine if dose escalation improves outcomes for chondrosarcomas (CHS) of the base of the skull (BOS) and the cervical spine (CS).

Methods: A prospective, randomized, dose-escalation trial was designed for patients with CHS of the BOS and CS. Patients were randomly assigned to 70 Gy (RBE) or 76 Gy (RBE). The primary endpoint was local failure (LF). Secondary endpoints included overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), and treatment-related toxicities.

Results: Between 1987 and 2007, 105 patients were randomized, median follow-up was 29.2 years (IQR, 26.7-32.4). Forty-six patients were assigned to 70 Gy (RBE) and fifty-nine were assigned to 76 Gy (RBE). LF at 5-, 10-, and 20 years were 7%, 9%, and 11% for 70 Gy (RBE), and 10%, 15%, and 19% for 76 Gy (RBE) (p = 0.16). Like LF rates, there was no benefit in dose escalation for OS (p = 0.28) and CSS (p = 0.22). Progression-free survival at 5-, 10-, and 20 years was 93%, 89%, and 77% for the low-dose group and 83%, 71%, and 59% for the high-dose group (p = 0.069). Late RT injury ≥ grade 3 was reported in a total of 19 (18%) patients across both dose levels, with 11% in the low-dose group and 24% in the high-dose group (p = 0.13).

Conclusions: This is the first and largest trial of patients with grade I/II BOS and CS CHS evaluating dose escalation for tumor control. Proton-based RT is effective and safe for these tumors, but there is no apparent benefit in dose escalation.

Background: The prognostic and predictive value of O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation is not well established in isocitrate dehydrogenase (IDH)-mutant gliomas. This study evaluates the survival impact of MGMTp and other clinical, molecular, and radiologic variables in low-grade and high-grade IDH-mutant gliomas.

Methods: We retrospectively evaluated 520 consecutive adult patients treated for an initial diagnosis of IDH-mutant glioma, of any histological grade, at two large academic institutions. MGMTp methylation was evaluated by methylation-specific polymerase chain reaction (PCR) analysis. Log-rank test and Cox proportional hazards model were applied to evaluate the association of clinical, molecular, and radiological characteristics with overall survival (OS) and progression-free survival (PFS).

Results: Median age was 36.6 years; MGMTp was methylated in 70% and unmethylated in 30%. MGMTp methylation was not significantly associated with PFS (p = 0.74) but trended towards significance for OS (p = 0.11) on multivariate analyses. Cyclin dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion [HR = 3.26 (1.47, 7.23, p = 0.006] and an integrated grade 4 classification [HR = 2.08 (1.06, 4.67), p = 0.048] were strong predictors of OS in astrocytoma, whereas maximal resection [HR = 0.06 (0.01, 0.57), p = 0.016] and radiation [HR = 0.41 (0.18, 0.91), p = 0.03] were strong prognosticators for PFS in the entire cohort. Maximal resection of the enhancing disease [HR = 0.17 (0.05, 0.96), p = 0.014] and radiation [HR = 0.47 (0.19, 0.65), p = 0.046] were strongly associated with PFS in grade 2 and 3 gliomas.

Conclusion: MGMTp methylation was not associated with a prognostic or predictive value in our IDH-mutant glioma cohort. CDKN2A/B status and extent of resection were strong predictors of outcomes.

Background: Tumor budding (TB) is a well established prognostic indicator in various epithelial malignancies. Chordoma, although a rare mesenchymal tumor, paradoxically exhibits prominent epithelial-like characteristics, as demonstrated in previous studies. In particular, it remains unclear whether TB like (TBL) structures are present in chordoma, as well as the molecular mechanisms driving their formation and their functional impact on tumor progression, representing a critical gap in current knowledge.

Methods: TBL grades were defined and evaluated in tumor specimens from 481 chordoma patients across four large cohorts using hematoxylin-eosin and immunohistochemical staining. Multi-omics profiling, encompassing GeoMx digital spatial profiling, spatial transcriptomics, bulk RNA sequencing, single-cell RNA sequencing, single-cell ATAC sequencing, and multiplex quantitative immunofluorescence, was integrated to delineate TBL cell subpopulation (TBLCs) and their interactions with cholesterol-metabolic tumor-associated macrophages (CM-TAMs). Organoid models and in vitro/in vivo functional assays were employed for mechanistic investigation and validation.

Results: TBL structures were prevalent in chordoma, and higher TBL grades were associated with unfavorable clinical outcomes and aggressive phenotypes. Mechanistically, BACH1 in CM-TAMs drove ANGPTL4 secretion, which targeted the SDC4 receptor on TBLCs, thereby enhancing stem-like properties, promoting cholesterol accumulation, and accelerating malignant progression. Pharmacological inhibition of cholesterol metabolism or disruption of the BACH1-ANGPTL4-SDC4 signaling axis markedly reduced tumor invasiveness in both preclinical models and chordoma organoids.

Conclusions: BACH1-driven CM-TAMs activate TBLCs via the ANGPTL4-SDC4 signaling axis, promoting stemness and cholesterol accumulation, ultimately driving malignant progression in chordoma. These findings uncover a previously unrecognized tumor-immune-metabolic interaction and suggest potential therapeutic targets for this disease.