Neuro-oncology最新文献

Background: Chordomas are rare, aggressive tumors of notochordal origin, commonly affecting the spine and skull base. Skull base chordomas (SBCs) comprise approximately 39% of cases, with an incidence of less than 1 per million annually in the United States. Prognosis remains poor due to resistance to chemotherapy, often requiring extensive surgical resection and adjuvant radiotherapy. Current classification methods based on chromosomal deletions are invasive and costly, presenting a need for alternative diagnostic tools. Radiomics allows for noninvasive SBC diagnosis and treatment planning.

Methods: We developed and validated radiomic-based models using MRI data to predict overall survival (OS) and progression-free survival following surgery (PFSS) in SBC patients. Machine-learning classifiers, including eXtreme Gradient Boosting (XGBoost), were employed along with feature selection techniques. Unsupervised clustering identified radiomic-based subgroups, which were correlated with chromosomal deletions and clinical outcomes.

Results: Our XGBoost model demonstrated superior predictive performance, achieving an area under the curve (AUC) of 83.33% for OS and 80.36% for PFSS, outperforming other classifiers. Radiomic clustering revealed two SBC groups with differing survival and molecular characteristics, strongly correlating with chromosomal deletion profiles. These findings indicate that radiomics can noninvasively characterize SBC phenotypes and stratify patients by prognosis.

Conclusions: Radiomics shows promise as a reliable, noninvasive tool for the prognostication and classification of SBCs, minimizing the need for invasive genetic testing and supporting personalized treatment strategies.

Background: PBTC-029B was a phase 2 trial evaluating efficacy of selumetinib in children with recurrent/progressive low-grade glioma. We report results of strata 2, 5, and 6 with updated survivals for strata 1, 3, and 4.

Methods: Stratum 2 included recurrent/progressive pilocytic astrocytoma (PA) not associated with neurofibromatosis type-1 (NF1) that screened negative for the BRAF-KIAA1549 fusion and BRAFV600E mutation. Stratum 5 enrolled non-PA that screened positive for one of the BRAF aberrations. Stratum 6 enrolled children who consented to tissue screening, but there was an assay failure. For long-term survivals, stratum 1 included non-NF1 PA positive for one of the BRAF aberrations; stratum 3 included NF1-associated pLGG; and stratum 4 included non-NF1 optic pathway/hypothalamic tumors.

Results: Stratum 2: among 14 evaluable patients, there was 1 partial response (PR), 7 stable disease (SD), and 6 progressive disease (PD); the overall response rate (ORR) was 7.1%. Two-year progression-free survival (PFS)/overall survival (OS) were 57.1%/100%, respectively. Stratum 5: among 23 evaluable patients, there was 1 complete response (CR), 4 PR, 12 SD, and 6 PD; ORR was 21.7%. Two-year PFS/OS were 74.8%/100%, respectively. Stratum 6: among 26 evaluable patients, there were 7 PR, 14 SD, and 5 PD; ORR was 26.9%. Two-year PFS/OS were 72.0%/100%, respectively. The median follow-up for patients on strata 1, 3, and 4 without events are 60.4, 60.4, and 58.1 months, and 5-year PFS/OS were 30.8%/88.9%, 54.2%/100%, and 51.0%/100%, respectively.

Conclusions: Selumetinib provided stability and responses across many pLGG subgroups, and some patients achieved prolonged disease control without additional therapy.

Background: Glioblastoma (GBM) represents a complex ecosystem characterized by numerous interactions between tumor cells and the surrounding tumor microenvironment (TME). Here, we show that WNT10A, a member of the WNT family, plays an important role in GBM growth where its influence is mediated via both autocrine and paracrine pathways thereby stimulating not only the tumor cells but also normal cell types within the tumor microenvironment (TME).

Methods: In silico analysis was performed to identify high-expressing WNT family members in GBM. Knockdown and overexpression methods were used to examine the function of WNT10A in GBM cells and in orthotopic GBM xenografts in vivo. Co-immunoprecipitation (Co-IP) was used to confirm receptor binding and chromatin immunoprecipitation (ChIP) was performed to analyze transcriptional activation of downstream genes.

Results: WNT10A was found to be highly expressed in GBMs and its knockdown significantly suppressed GBM malignant behavior in vitro and in vivo. Co-IP assays confirmed an interaction between WNT10A and FZD1, which activated the JNK/c-Jun/FOSB signaling pathway and enhanced the transcription of FOSB. Importantly, GBM cells secreted WNT10A into the tumor microenvironment, leading to an activation of the PI3K-AKT pathway in tumor-associated macrophages (TAMs) and the JNK pathway in tumor-associated astrocytes. The latter caused a secretion of tumor-promoting cytokines IL-6, MCP-1, and angiogenin. LGK974, a PORCN inhibitor, inhibited the secretion of WNT10A to suppress the malignant GBM phenotype.

Conclusions: Our findings revealed that WNT10A is a critical factor in promoting GBM progression through both autocrine and paracrine mechanisms. Thus, our findings provide the foundation for WNT-targeted clinical GBM treatment.

Background: Therapeutic resistance in glioblastoma (GBM) is multifactorial and results from genetic heterogeneity, the immunoprivileged localization, and the potently tolerogenic microenvironment. Signal transducer and activator of transcription 3 (STAT3) plays a key role in both glioma cell survival and immune evasion, reinforcing GBM resistance.

Methods: Here, we describe a new cell-selective and double-stranded STAT3 antisense oligonucleotide (CpG-STAT3dsASO) for targeting human/mouse glioma cells and GAMs but not T cells. The oligonucleotide safety and efficacy against orthotopic GBM was assessed in immunocompetent or immunodeficient mice.

Results: CpG-STAT3dsASO injected intracranially/intratumorally was well-tolerated and reduced progression of human U251 GBM xenotransplants and mouse GL261 or neural cell-derived QPP8 gliomas. Unlike the single-stranded oligonucleotide, local CpG-STAT3dsASO administration did not trigger type-I IFN-dependent neurotoxicities in immunocompetent mice within the therapeutic dose range. CpG-STAT3dsASO activated intratumoral GAMs, such as dendritic cells, macrophages and microglia, thereby expanding CD4+ Th1 cells while reducing TREG numbers. CpG-STAT3dsASO monotherapy did not have curative effects as it led to recruitment of only limited numbers of mostly exhausted effector CD8+ T cells. However, when combined with systemic PD1 inhibition, CpG-STAT3dsASO/anti-PD1 treatments caused regression of GL261 as well as immunotherapy-resistant QPP8 gliomas and resulted in long-term survival of the majority of mice. The combination treatment boosted CD8+ effector T-cell activity, while promoting their intratumoral interaction with activated CD4+ Th1 cells and activated macrophages as indicated by spatial transcriptomics.

Conclusions: Our results suggest rationale for GBM immunotherapy using CpG-STAT3dsASO to disrupt GAMs-dependent immune evasion, thereby restoring sensitivity to PD1 blockade and facilitating T-cell-mediated antitumor immune responses.

Background: Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neuroendocrine tumors. PitNETs can be challenging to classify, and current recommendations include a large immunohistochemical panel to differentiate among 14 WHO-recognized categories.

Methods: In this study, we analyzed clinical, immunohistochemical, and DNA methylation data of 118 PitNETs to develop a clinicomolecular approach to classifying PitNETs and identifying epigenetic classes.

Results: CNS DNA methylation classifier has an excellent performance in recognizing PitNETs and distinguishing the 3 lineages when the calibrated score is ≥ 0.3. Unsupervised DNA methylation analysis separated PitNETs into 2 major clusters. The first was composed of silent gonadotrophs, which form a biologically distinct group of PitNETs characterized by clinical silencing, weak hormonal expression on immunohistochemistry, and simple copy number profile. The second major cluster was composed of corticotrophs and Pit1 lineage PitNETs, which could be further classified using DNA methylation into distinct subclusters that corresponded to clinically functioning and silent tumors and are consistent with transcription factor expression. Analysis of promoter methylation patterns correlated with lineage for corticotrophs and Pit1 lineage subtypes. However, the gonadotrophic genes did not show a distinct promoter methylation pattern in gonadotroph tumors compared to other lineages. Promoter of the NR5A1 gene, which encodes SF1, was hypermethylated across all PitNETs clinical and molecular subtypes including gonadotrophs with strong SF1 protein expression indicating alternative epigenetic regulation.

Conclusion: Our findings suggest that classification of PitNETs may benefit from DNA methylation for clinicopathological stratification.

Background: Astrocytoma, isocitrate dehydrogenase-mutant, WHO grade 4 (Astro4), is a new tumor type in the 2021 WHO classification of central nervous system tumors that has been poorly characterized in the literature. This study evaluates predictors of prognosis in a large cohort of newly diagnosed Astro4.

Methods: We retrospectively identified 128 consecutive adult patients who presented with an initial diagnosis of Astro4 at Dana-Farber Cancer Institute and Massachusetts General Hospital between 2010 and 2021. Clinical, molecular, and radiological characteristics were recorded, and their associations with overall survival (OS) and progression-free survival (PFS) were measured by log-rank test and Cox proportional hazards model.

Results: The median age at diagnosis was 37.1 years, and 61.7% were men. The median OS was 5.9 years (95% confidence interval, 4.4-7.3), while the median PFS was 2.7 years (1.8 -3.6). Age ≥ 50 and homozygous CDKN2A/B deletion were independent negative prognosticators of OS on univariate and multivariate analyses (hazard ratio [HR], 2.21 [1.16-4.21], P = .019; HR, 2.61 [1.27-5.38], P = .013). Maximal resection of enhancing disease was associated with longer PFS on univariate and multivariate analyses (HR, 0.48 [0.26-0.87], P = .019). There were no significant differences in OS or PFS based on MGMT promoter methylation status, T2/FLAIR extent of resection, T2/FLAIR mismatch, radiological pseudoprogression, or enhancement on the pre-operative scan.

Conclusions: Our study comprehensively characterizes a large cohort of newly diagnosed patients with Astro4, emphasizing the prognostic value of CDKN2A/B deletion, age, and the extent of resection of enhancing disease in these patients.