Neuro-oncology最新文献

Background: Co-amplification of EGFR and EGFRvIII, a tumor-specific truncation mutant of EGFR, represent hallmark genetic lesions in glioblastoma.

Methods: We used phospho-proteomics, RNA-sequencing, TCGA data and glioblastoma cell culture and mouse models to study the signal transduction mediated by EGFR and EGFRvIII.

Results: We report that EGFR and EGFRvIII stimulate the innate immune defense receptor Toll-like Receptor 2 (TLR2); and that knockout of TLR2 dramatically improved survival in orthotopic glioblastoma xenografts. EGFR and EGFRvIII activated TLR2 in a ligand-independent manner, promoting tumor growth and immune evasion. We show that EGFR and EGFRvIII cooperate to activate the Rho-associated protein kinase ROCK2, which modulated malignant progression both by activating TLR2 and WNT signaling, and through remodeling the tumor microenvironment.

Conclusion: Together, our findings show that EGFR and EGFRvIII cooperate to drive tumor progression through ROCK2 and downstream WNT-β-catenin/TLR2 signaling pathways.

Background: Patients with primary brain tumors demonstrate heterogeneous patterns of cognitive dysfunction, which we explore using latent profile analysis (LPA) to identify cognitive phenotypes and their trajectories in patients receiving radiotherapy (RT).

Methods: Ninety-six patients completed neuropsychological testing before and post-RT (3, 6, 12-months) on a prospective longitudinal trial, including measures of processing speed, executive function, language, and verbal and visual memory. Models with 2-4 classes were examined. Demographic and clinical data were examined across phenotypes and post-RT cognitive change was evaluated.

Results: The optimal model identified three unique cognitive phenotypes including a group of patients with generalized impairments (11.5%), a group with isolated verbal memory impairments (21.9%), and a group with minimal impairments (66.7%). The Verbal Memory phenotype had fewer years of education (p=.007) and a greater proportion of males (p<.001); the Generalized group had a greater proportion of patients with IDH-wild type gliomas and showed greater symptoms of anxiety and poorer quality of life (p-values<.05); and the Minimal Impairment phenotype had higher rates of IDH-Mutant gliomas. Approximately 50% of patients declined on at least one cognitive domain with memory the most vulnerable. Patients that declined reported greater symptoms of depression (p=.007) and poorer quality of life (p=.025).

Conclusions: We identified three distinct cognitive phenotypes in patients with primary brain tumors receiving RT, each associated with unique demographic and clinical (e.g., IDH mutational status) profiles, with mood symptoms associated with late cognitive decline. This patient-centered approach enhances our understanding of clinical profiles associated with cognitive dysfunction and treatment-related neurotoxicity.

MR imaging is central to the assessment of tumor burden and changes over time in neuro-oncology. Several response assessment guidelines have been set forth by the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working groups in different tumor histologies; however, the visual delineation of tumor components using MRIs is not always straightforward, and complexities not currently addressed by these criteria can introduce inter- and intra-observer variability in manual assessments. Differentiation of non-enhancing tumors from peritumoral edema, mild enhancement from absence of enhancement, and various cystic components can be challenging; particularly given a lack of sufficient and uniform imaging protocols in clinical practice. Automated tumor segmentation with artificial intelligence (AI) may be able to provide more objective delineations, but rely on accurate and consistent training data created manually (ground truth). Herein, this paper reviews existing challenges and potential solutions to identifying and defining subregions of pediatric brain tumors (PBTs) that are not explicitly addressed by current guidelines. The goal is to assert the importance of defining and adopting criteria for addressing these challenges, as it will be critical to achieving standardized tumor measurements and reproducible response assessment in PBTs, ultimately leading to more precise outcome metrics and accurate comparisons among clinical studies.

Background: Surgical resection is the standard of care for patients with large or symptomatic brain metastases (BMs). Despite improved local control after adjuvant stereotactic radiotherapy, the risk of local failure (LF) persists. Therefore, we aimed to develop and externally validate a pre-therapeutic radiomics-based prediction tool to identify patients at high LF risk.

Methods: Data were collected from A Multicenter Analysis of Stereotactic Radiotherapy to the Resection Cavity of BMs (AURORA) retrospective study (training cohort: 253 patients from 2 centers; external test cohort: 99 patients from 5 centers). Radiomic features were extracted from the contrast-enhancing BM (T1-CE MRI sequence) and the surrounding edema (T2-FLAIR sequence). Different combinations of radiomic and clinical features were compared. The final models were trained on the entire training cohort with the best parameter set previously determined by internal 5-fold cross-validation and tested on the external test set.

Results: The best performance in the external test was achieved by an elastic net regression model trained with a combination of radiomic and clinical features with a concordance index (CI) of 0.77, outperforming any clinical model (best CI: 0.70). The model effectively stratified patients by LF risk in a Kaplan-Meier analysis (P < .001) and demonstrated an incremental net clinical benefit. At 24 months, we found LF in 9% and 74% of the low and high-risk groups, respectively.

Conclusions: A combination of clinical and radiomic features predicted freedom from LF better than any clinical feature set alone. Patients at high risk for LF may benefit from stricter follow-up routines or intensified therapy.

Background: The FDA approval of oncolytic herpes simplex-1 virus (oHSV) therapy underscores its therapeutic promise and safety as a cancer immunotherapy. Despite this promise, the current efficacy of oHSV is significantly limited to a small subset of patients largely due to the resistance in tumor and tumor microenvironment (TME).

Methods: RNA sequencing (RNA-Seq) was used to identify molecular targets of oHSV resistance. Intracranial human and murine glioma or breast cancer brain metastasis (BCBM) tumor-bearing mouse models were employed to elucidate the mechanism underlying oHSV therapy-induced resistance.

Results: Transcriptome analysis identified IGF2 as one of the top-secreted proteins following oHSV treatment. Moreover, IGF2 expression was significantly upregulated in 10 out of 14 recurrent GBM patients after treatment with oHSV, rQNestin34.5v.2 (71.4%; P = .0020) (ClinicalTrials.gov, NCT03152318). Depletion of IGF2 substantially enhanced oHSV-mediated tumor cell killing in vitro and improved survival of mice bearing BCBM tumors in vivo. To mitigate the oHSV-induced IGF2 in the TME, we constructed a novel oHSV, oHSV-D11mt, secreting a modified IGF2R domain 11 (IGF2RD11mt) that acts as IGF2 decoy receptor. Selective blocking of IGF2 by IGF2RD11mt significantly increased cytotoxicity, reduced oHSV-induced neutrophils/PMN-MDSCs infiltration, and reduced secretion of immune suppressive/proangiogenic cytokines, while increased CD8 + cytotoxic T lymphocytes (CTLs) infiltration, leading to enhanced survival in GBM or BCBM tumor-bearing mice.

Conclusions: This is the first study reporting that oHSV-induced secreted IGF2 exerts a critical role in resistance to oHSV therapy, which can be overcome by oHSV-D11mt as a promising therapeutic advance for enhanced viro-immunotherapy.

Background: Immune checkpoint inhibitors (ICIs) have efficacy in several solid tumors but limited efficacy in glioblastoma (GBM). This study evaluated the safety of anti-CTLA-4 and anti-PD-1 ICIs alone or in combination in newly diagnosed GBM after completion of standard radiochemotherapy with the subsequent intent to test combinatorial ICIs in this setting.

Methods: The primary endpoint was dose-limiting toxicity (DLT) for adults with unifocal, supratentorial newly diagnosed GBM after resection and chemoradiation. Ipilimumab and nivolumab were tested separately and in combination with a planned expansion cohort dependent upon DLT results.

Results: Thirty-two patients were enrolled at 9 institutions: 6 to each DLT assessment cohort and 14 to the expansion cohort. Median age: 55 years, 67.7% male, 83.9% White. Treatment was well tolerated with 16% Grade 4 events; the combination did not have unexpectedly increased toxicity, with no Grade 5 events. One DLT was seen in each single-agent treatment; none were observed in the combination, leading to expanded accrual of the combined treatment. The median follow-up was 19.6 months. For all patients receiving combination treatment, median overall survival (OS) and progression-free survival (PFS) were 20.7 and 16.1 months, respectively.

Conclusions: IPI and NIVO are safe and tolerable with toxicities similar to those noted with other cancers when given in combination with adjuvant temozolomide for newly diagnosed GBM. Combination IPI + NIVO is not substantially more toxic than single agents. These results support a subsequent efficacy trial to test the combination of ICIs in Phase II/III for patients with newly diagnosed GBM.

Clinicaltrials.gov registration: NCT02311920.

Background: Cranial radiotherapy is standard of care for high-grade brain tumors and metastases; however, it induces debilitating neurocognitive impairments in cancer survivors, especially children. As the numbers of pediatric brain cancer survivors continue improving, the numbers of individuals developing life-long neurocognitive sequalae are consequently expected to rise. Yet, there are no established biomarkers estimating the degree of the irradiation-induced brain injury at completion of radiotherapy to predict the severity of the expected neurocognitive complications. We aimed to identify sensitive biomarkers associated with brain response to irradiation that can be measured in easily accessible clinical materials, such as liquid biopsies.

Methods: Juvenile mice were subjected to cranial irradiation with 0.5, 1, 2, 4, and 8 Gy. Cerebrospinal fluid (CSF), plasma, and brains were collected at acute, subacute, and subchronic phases after irradiation, and processed for proteomic screens, and molecular and histological analyses.

Results: We found that the levels of ectodysplasin A2 receptor (EDA2R), member of tumor necrosis factor receptor superfamily, increased significantly in the CSF after cranial irradiation, even at lower irradiation doses. The levels of EDA2R were increased globally in the brain acutely after irradiation and decreased over time. EDA2R was predominantly expressed by neurons, and the temporal dynamics of EDA2R in the brain was reflected in the plasma samples.

Conclusions: We propose EDA2R as a promising potential biomarker reflecting irradiation-induced brain injury in liquid biopsies. The levels of EDA2R upon completion of radiotherapy may aid in predicting the severity of IR-induced neurocognitive sequalae at a very early stage after treatment.