Neuro-oncology最新文献

Background: Improving the surgical outcomes for commonly occurring spinal neoplasms of extradural and intradural extramedullary origins requires precise intraoperative diagnosis provided by highly trained neuropathologists.

Methods: Through a retrospective study of n=319 patient specimens, verified where appropriate by learning curve analysis to be sufficient for statistically significant observations, we aimed to assess the utility of 10-second picosecond infrared laser mass spectrometry (PIRL-MS) for non-subjective diagnosis of major spinal tumour types of metastatic carcinoma, schwannoma and meningiomas.

Results: The sensitivity and specificity values of spinal tumour type diagnosis (based on n=182 independent specimens) were (93±1)% and (97±2)%, respectively. This classification utilizes n=41 cellular lipids including phosphatidylcholines, sphingomyelins, phosphatidylethanolamines, and ceramides whose identities were established using high-resolution tandem mass spectrometry. Furthermore, the accuracy of diagnosis of a model that contained n=97 meningioma and n=106 schwannoma was not drastically influenced by the presence of n=54 additional intradural extramedullary spinal neoplasms of myxopapillary ependymoma, neurofibroma, paraganglioma and solitary fibrous tumour types in the differential diagnosis, confirming the generalizability and robustness of the identified molecular array in rendering correct classification even in the presence of data not seen previously by the model.

Conclusions: The identified lipids form a 'molecular array' for robust diagnosis of meningioma and schwannoma tumours by non-pathologists in a manner similar to genomic, transcriptomic or methylomic arrays used to diagnose brain cancer types, albeit on a much faster timescale of seconds as opposed to hours.

Background: The end-of-life (EoL) phase of care is inevitable for glioblastoma (GBM) patients; however, it lacks standardization. This study aimed to characterize the utilization of care at EoL in GBM patients, focusing on trends over time, regional variability, and the influence of socioeconomic factors.

Methods: This was a retrospective population-based cohort study of all patients with GBM treated in Ontario between 1994 - 2018 using administrative health data and registries available at ICES (formerly the Institute for Clinical Evaluative Sciences). The proportion of patients with palliative care, supportive care, and in-hospital deaths by year of diagnosis was estimated, and trends assessed with the Cochrane-Armitage trend test.

Results: The cohort included 9,013 GBM patients. There was an increase in supportive care components over the study time-period (29.6% in 1994 - 1998 to 60.2% in 2014 - 2018; p < 0.0001). There was a simultaneous decrease in in-hospital deaths (50.5% in 1994 - 1998 to 21.4% in 2014 - 2018; p<0.001) and hospitalizations within 30 days before death (65.5% in 1994-1998 to 51.7% in 2014 - 2018, p<0.001). This coincided with an increased in chemotherapy administration within 14 days of death and ICU admissions within 30 days of death over the studied period of time. Patient neighborhood income level and geographic location influenced EoL care patterns with regards to both supportive and aggressive components.

Conclusions: Over time there was an expansion of both inpatient and outpatient palliative care use at EoL. Rurality and neighborhood income quintile significantly influenced the utilization of these resources, underscoring the need for standardized EoL care practices.

Background: Median survival for patients with Diffuse Intrinsic Pontine Glioma (DIPG) is 8-12 months.

Methods: A phase 1, open label, 3 + 3 dose escalation trial delivered radiolabeled 124I-Omburtamab, targeting B7-H3, using MR-guided stereotactic convection enhanced delivery (CED) into the brainstem of pediatric DIPG patients. CED was performed after completion of standard-of-care external-beam radiation therapy (EBRT). Fifty children were treated and evaluable. 124I-Omburtamab activity was escalated from 0.25-10.0 mCi (9.25-370 MBq) and volume escalated from 0.25 ml-10.0 ml with serial PET/MRI post-administration. Safety was the primary outcome. National Cancer Institute Common Terminology Criteria for Adverse Events were assessed for 30 days following CED of 124I-Omburtamab. Secondary outcomes included overall survival and lesion-to-whole-body absorbed dose ratio.

Results: The maximum tolerated activity per study protocol was determined to be 6mCi (222 MBq). The overall mean (±SD) total absorbed dose in the lesion per unit injected activity was 35.2 ± 18 cGy/MBq with a high lesion-to-whole-body absorbed dose ratio averaging 816, across all activity levels. Eleven patients had treatment-related grade 3 CNS toxicities with no grade-4 or -5 CNS toxicities. Five dose-limiting toxicity events occurred. Median survival was 15.29 months from diagnosis (95% CI: 12.20 - 16.83 months). Survival rate estimates at 1, 2, and 3 years were 65.4% (CI 53.3-80.1%), 18.4% (CI: 10.2-33.2%), and 11.7% (CI: 5.3-25.7%), respectively.

Conclusions: Administration of 124I-Omburtamab via CED is a safe treatment option for DIPG, with a maximum tolerated activity level identified. This study represents the first in-human theranostic use of a 124I radiopharmaceutical, simultaneously, as an imaging and therapeutic agent.

Background: Recent studies have highlighted bidirectional signalling between tumours and neurons; however, the interactions between tumours and neurons in response to radio-/chemotherapy remain obscure, which hampers the tumour treatment.

Methods: Glioblastoma organoids (GBOs) and primary neuron coculture, targeted metabonomics, RNA pulldown, mass spectrum, co-immunoprecipitation, RNA-sequencing, transcript/protein validations and multi-electrode arrays were performed to analyse neuron-tumour interaction in response to therapy. In vivo validations were conducted in orthotopic mouse models. Diagnostic and prognostic values were evaluated in serum, tissue-microarray as well as TCGA.

Results: GBOs recruited and induced pro-tumour-survival senescent neurons upon radiation/chemotherapeutic treatment. Targeted metabonomics revealed that significantly increased tumour-derived prostaglandin E2 (PGE2) induced neuronal senescence phenotype. Screening of enzymes involved in PGE2 synthesis identified prostaglandin E synthase 3 (PTGES3) as the key enzyme responsible for PGE2 upregulation. Biochemical studies revealed that irradiation or chemotherapeutic drug-triggered asparagine endopeptidase (AEP) specifically cleaved eIF4A1 to produce teIF4A1-C, which dissociated from DDX6 and recruited eIF4A3 and PABPN1 to promote the mRNA stability of PTGES3. Elevated PGE2 reciprocally enhanced AEP expression. Inhibiting PGE2 or AEP reduced neuronal senescence and delayed tumour progression. Strikingly, single-cell analysis further showed that expressions of AEP/PTGES3/EIF4A1 in tumour cells were consistent with senescent neuronal CDKN1A in high-neuronal-connectivity glioblastoma. The serum PGE2 concentration was elevated after radiation and higher in resistant glioblastoma patients. High expression of PTGES3 was associated with a poor prognosis.

Conclusions: Our study revealed that the AEP/PGE2 feedback loop modulates tumour-induced neuronal senescence upon radio-/chemotherapy and highlight the therapeutic value to improve tumour therapy.

Introduction: This study determines the relationship between diffusion and perfusion-based MRI signatures and radio-pathomic maps of tumor pathology in a large, multi-site cohort.

Methods: This study included perfusion imaging from pre-surgical relative cerebral blood volume (rCBV) images from the UPenn-GBM dataset and pre-surgical arterial spin labeling (ASL) imaging from the UCSF-PDGM dataset. Diffusion imaging included fractional anisotropy (FA) estimates derived from diffusion tensor imaging (DTI) for each subject from each institution. A previously validated autopsy-based model was applied to the structural images from each patient to generate quantitative radio-pathomic maps of cell density and extracellular fluid (ECF). Mean cell density, ECF density, FA, rCBV calculated from DSC imaging, and rCBF calculated from ASL were computed for each patient and statistically compared within contrast-enhancement (CE) and the non-enhancing peritumor FLAIR hyperintensity (FH).

Results: Both rCBV and ASL showed positive correlation with cell density within CE (rCBV: R=0.280, p<0.001; ASL: R=0.117, p=0.023). However, both perfusion metrics also showed no association with cell density within the FH region at the group level (rCBV: R=0.0162, p=0.731; ASL: R=-0.020, p=0.652). Negative correlations were observed between FA and ECF density across both CE and FH in both the UPenn-GBM (CE: r = -0.204, p<0.001, FH: r=-0.332, p<0.001) and the UCSF-PDGM (CE:r=-0.179, p<0.001, FH:-0.355, p<0.001). Additionally, a positive ASL-cell density association per subject within FH was associated with worse survival prognosis (HR=5.58, p=0.022).

Discussion: These results suggest that radio-pathomic maps of tumor pathology provide complementary information to other MR signatures that reveal prognostically valuable signatures of the non-enhancing tumor margin.

Background: Despite numerous studies on medulloblastoma (MB) cell heterogeneity, the spatial characteristics of cellular states remain unclear.

Methods: We analyze single-nucleus and spatial transcriptomes and chromatin accessibility from human MB spanning four subgroups, to identify malignant cell populations and describe the spatial evolutionary trajectories. The spatial CNVs patterns and niches were analyzed to investigate the cellular interactions.

Results: Three main malignant cell populations were identified, including progenitor-like, cycling and differentiated populations. Gene signatures of cell populations strongly correlate to clinical outcomes. These tumor cell populations are geographically organized as stem-like and mature regions, highlighting their spatially heterogeneous nature. Progenitor-like and cycling cells are mainly concentrated in stem-like regions, whereas various differentiated populations are primarily distributed in mature regions. By analyzing chromosomal alterations, we find that stem-like region typically harbors a single pattern of CNVs, reflecting high originality and uniformity, which is in stark contrast to mature region exhibiting multiple patterns with a broader range of biological functions. Projecting cellular state program onto spatial sections fully illustrates the evolution from stem-like region to various functional zones in mature region, which is correlated to microenvironmental components along the paths to maintain stemness or promote differentiation. Conclusions. This multi-omics database comprehensively facilitates the understanding of MB spatial evolutionary organization.

Background: Diffuse Midline Glioma (DMG) is a highly aggressive pediatric brain tumor with limited treatment options despite extensive genomic characterization. The aim of this study was to investigate the proteomic landscape of DMG to identify potential therapeutic targets.

Methods: We conducted a comprehensive proteomic analysis using LC-MS3, along with DNA methylation and DNA/RNA sequencing in 55 DMG patients' samples. PTM profiling (phosphoproteome and methylproteome) was conducted in 30 patient samples. We then investigated the effects of modulating key protein targets on protein methylation, protein synthesis, and DMG cell growth in vitro and in vivo.

Results: DMGs exhibited high global protein methylation, with significant enrichment of translation machinery proteins and factors involved in apoptosis regulation. Surprisingly, while targets of key kinases were highly phosphorylated, overall protein phosphorylation was lower in DMG compared to normal brain tissues. Non-histone methyltransferases METTL13 and METTL21B, along with protein kinases PAK2, PRKACA, and AKT1, were identified as key players in DMG methylproteome and phosphoproteome, respectively. METTL13 knockdown led to reduced EEF1A1 protein methylation, a shift in oncoprotein synthesis, and inhibited DMG cell growth in vitro and in vivo.

Conclusions: Our findings highlight the dependency of DMG on methyl-signaling pathways, particularly involving METTL13, which regulates EEF1A1 protein methylation and oncoprotein synthesis. Targeting the non-histone methyltransferases offers a promising therapeutic strategy for DMG. This study underscores the potential of post-translational modifications, specifically methyl-signaling pathways, as novel therapeutic targets for DMG and possibly other currently incurable cancers.

Background: Brainstem gliomas (BSGs) harboring a histone 3 lysine27-to-methionine (H3K27M) mutation represent one of the deadliest brain tumors with a dismal prognosis, as they exhibit a much worse response to therapy compared to the wildtype BSGs. Early non-invasive recognition of the H3K27M mutation is paramount for clinical decision-making in treating BSGs.

Methods: Plasma and urine samples were prospectively collected from BSG patients before biopsy or surgical resection and were chronologically divided into discovery, test, and validation cohorts. Utilizing the discovery and test cohort samples, an untargeted metabolomic strategy was exploited to identify candidate metabolite biomarkers, related to the H3K27M mutation. The candidate biomarkers were validated in the validation cohort with a targeted metabolomic method.

Results: Differential metabolomic profiles were detected between the H3K27M-mutant and wild-type BSGs in both the plasma and urine, the metabolomic changes were more dramatic in urine than in plasma. After rigorous screening for candidate biomarkers and validation with a targeted metabolomic approach, three metabolites, nomilin, Lys-Leu, and hawkinsin, emerged as significantly elevated biomarkers in H3K27M-mutant BSG urine samples. The biomarker panel combining the three metabolites had a diagnostic area under the curve (AUC) of approximately 75%. Furthermore, the biomarker panel improved the prediction accuracy of radiomics/clinical models to an AUC value high as 93.38%.

Conclusions: A urinary metabolite biomarker panel that exhibited high accuracy for non-invasive prediction of the H3K27M mutation status in BSG patients was identified. This panel has the potential to improve the predictive performance of current radiomics models or clinical features.

Background: Spinal hemangioblastomas (sHBs) are rare vascular tumors with significant neurological implications. Their management, particularly in von Hippel-Lindau (VHL) disease, remains challenging due to recurrence and functional decline. Timely identification and intervention are critical for optimal outcomes.

Methods: This international, multicenter retrospective cohort study included 357 patients (199 VHL-associated, 158 sporadic) from 13 neuro-oncological centers. Clinical and imaging data were analyzed to assess progression-free survival (PFS) and functional outcomes using the Modified McCormick Scale (mMCS) at 12 months. Secondary analyses identified factors associated with VHL disease in sHBs.

Results: Complete resection (CR) was achieved in 87.7% of cases, leading to significantly improved PFS at 72 months (sporadic: 95.1%, VHL-associated: 91.1%; HR: 0.18, 95%CI: 0.08-0.4). Multivariable analysis identified predictors of unfavorable outcomes at 12 months: Preoperative mMCS ≥2 (OR: 5.17, p=0.008), intramedullary tumor location (OR: 9.48, p=0.01), and preoperative bleeding (OR: 31.12, p=0.02). Factors independently associated with VHL disease in sHBs included non-cervical tumor location (OR: 2.08, p=0.004), intramedullary growth (OR: 2.39, p<0.001), and age <43 years (OR: 3.24, p<0.001). Functional improvements were observed in most patients, particularly those with sporadic sHBs.

Conclusions: Complete surgical resection is essential for long-term tumor control and favorable functional outcomes in both sporadic and VHL-associated sHBs. Early intervention, particularly in mild symptomatic and progressive cases, before neurological deterioration or hemorrhage, optimizes recovery. This study, the largest of its kind in a multicentric international setting, provides robust evidence to guide the management of both sporadic and VHL-associated sHBs.