Neuro-oncology最新文献

Background: Extracranial metastases from adult gliomas cause diagnostic and therapeutic challenges and are generally poorly investigated. The aim of this study was to provide clinical and molecular insights into glioma metastasis.

Methods: Our cohort comprised tumor tissue from 16 glioma patients with metastasis (14 glioblastomas and 2 lower-grade gliomas). Paired primary tumors, recurrences, and metastases were investigated by DNA sequencing, genome-wide DNA methylation profiling, RNA sequencing, immunohistochemistry, and MRI examinations.

Results: The metastases were distributed across the scalp/upper neck (8), lymph nodes (5), bone (2), and liver (1). Six out of 14 glioblastomas displayed significant sarcomatous differentiation, consistent with the otherwise rare histological subtype gliosarcoma. A majority of the scalp lesions were connected to an intracranial brain tumor via tumor extension through craniotomy burr holes, proposing that surgery is a contributing factor to tumor spread. Next-generation sequencing-based mutational analysis revealed that the true metastases originated from the primary tumors and not later recurrences. We observed tumor plasticity as the tumors progressed to metastasis, demonstrated by changes in epigenetic methylation classes and transcriptional subtypes. Despite different locations of metastases in the cohort, the immune cell composition in the tumor microenvironment remained overall stable during tumor progression.

Conclusion: Metastases from adult gliomas originate from the primary brain tumors and not later recurrences. While RNA sequencing and methylation profiling revealed tumor plasticity during progression to metastasis, the immune cell composition remained overall stable.

Background: The identification of clinical and molecular heterogeneity in medulloblastoma has produced risk-stratified therapy, but establishing the most effective yet least toxic regimens has remained elusive owing to numerous treatment options. To improve risk-stratification, we performed an integrated analysis from three clinical trials.

Methods: Medulloblastoma patients from ACNS0331/NCT00085735, ACNS0332/NCT00392327, and SJMB03/NCT00085202 were included if they had methylation profiling. Molecular groups [WNT, SHH, Group 3 (G3), and Group 4 (G4)], subgroups, and copy number variations were procured from methylation profiles and mutations from next-generation sequencing. Data was assembled into an interactive portal to capture patient characteristics. Cross-trial comparisons, univariable, and multivariable analyses were conducted and used to derive a risk-stratification schema.

Results: Eight hundred ninety-eight patients (WNT = 131, SHH = 151, G3 = 220, G4 = 396) were included. Progression-free-survival (PFS) distributions among analogous cross-trial cohorts were not different, demonstrating no survival advantage of any one therapy over another. The addition of carboplatin to high-dose craniospinal irradiation (HDCSI) containing regimen was selectively superior in PFS in G3/G4 subgroup 3 (P = 0.048) and G3/G4 subgroup 2 (P = 0.035) to HDCSI regimens without carboplatin. Nine actionable risk-stratified groups were identified consisting of 2 WNT groups (low, high-risk), 3 SHH groups (low-, average-, very-high-risk), and 4 G3/G4 groups (low-, average-, high-, and very-high-risk).

Conclusions: Our integrated cross-trial analysis suggests toxicity can be reduced by eliminating disproportionate differences in therapy in favor of a more uniform treatment backbone. Moreover, we propose and model a risk-classification system that identifies the most appropriate cohorts on which to trial significant dose reductions in craniospinal irradiation or select treatment intensifications.

Background: Glioblastoma (GBM) may disrupt glymphatic function and neurofluid dynamics locally and in distant brain regions. However, the prognostic relevance of such alterations remains unclear. We investigated whether diffusion tensor image analysis along the perivascular space (DTI-ALPS) and free water (FW) imaging serve as biomarkers of glymphatic dysfunction and survival in patients with IDH wild-type GBM.

Methods: We retrospectively analyzed preoperative MRI data from 277 patients in the UPENN-GBM and 269 patients in the UCSF-PDGM cohorts. The ALPS index was quantified in tumor regions and normal-appearing white matter (NAWM) in both hemispheres, and the FW volume fraction in the contralateral NAWM. Data harmonization was performed using ComBat to adjust for intersite variability. Survival analyses were conducted using log-rank tests and Cox regression models. Optimal ALPS index and FW thresholds were derived from the UPENN-GBM dataset and validated in the UCSF-PDGM.

Results: The ALPS index was significantly lower in tumor regions than NAWM (P < .01). In the contralateral hemisphere of the UPENN-GBM cohort, a lower ALPS index and higher FW in NAWM were independently associated with shorter overall survival (HR = 0.75, P = .027 for ALPS index; HR = 1.34, P = .04 for FW). The identified thresholds successfully stratified survival in UPENN-GBM and were validated in UCSF-PDGM (P = .011 for ALPS; P = .038 for FW).

Conclusions: Neurofluid dynamic alterations in the contralateral hemisphere, assessed using DTI-ALPS and FW imaging, were independently associated with survival in patients with IDH wild-type GBM. These findings support the use of glymphatic imaging markers for prognostic stratification and therapeutic targeting.

Background: Positive effects of early integration of palliative care (EIPC) have been shown for systemic solid malignant tumors. We tested the hypothesis that EIPC improves quality of life (QoL), palliative care (PC) problems and mood in glioblastoma patients and reduces caregiver burden.

Methods: This randomized, rater-blinded, controlled trial conducted in six German university medical centers included glioblastoma patients within four weeks after diagnosis (first/recurrent) and their caregivers. Patients received standard care (control) or standard care and EIPC (intervention) for 12 months. Primary outcome was change in QoL after six months measured by the trial outcome index of the FACT-Br. Data were assessed 3-monthly for up to 24 months.

Results: Between 05/2019 and 04/2021 patients were enrolled and randomized to the intervention (n = 109) or control group (n = 108). QoL at month six was in favor of the intervention, however not statistically significant (mean difference 4.1 with 95% CI, -4.4 to 12.6, P = .34; intervention: n = 98 (m = 54/f = 44); control: n = 89 (m = 50/f = 39)). In an analysis adjusted for time of death, performed because of a significant survival difference (control superior to intervention, P = .018), QoL was better in the intervention group (P = .041). Secondary outcomes showed that patients significantly benefited from EIPC regarding PC problems and mood especially after intervention ended, while caregivers did not seem to benefit.

Conclusions: Provided that the survival difference is included in the analysis, EIPC improves QoL in glioblastoma patients. This, in addition to improved mood and PC problems, demonstrates that EIPC sustainably improves 'how to live' but not 'length of life'.

Background: Therapies for diffuse glioma induce DNA damage response (DDR), and strategies to exploit DDR defects are active areas of investigation. While global DNA methylation profiling effectively classifies gliomas into subtypes, the epigenetic and gene expression patterns of DDR genes, and their contribution to tumor classification and outcomes, have yet to be fully elucidated. Thus, dissecting the DDR epigenetics, gene expression, and single-cell heterogeneity may reveal key molecular characteristics, refine prognosis, and identify novel treatment strategies and resistance mechanisms.

Methods: We characterized DDR epigenetics and gene expression of TCGA glioblastomas (GBM) and low-grade gliomas (LGG). Single-cell protein analysis by imaging mass cytometry (IMC) was performed on a separate cohort of 118 diffuse gliomas.

Results: Analysis of TCGA cohorts revealed two DDR methylation groups that correlated with IDH mutation status and previously reported molecular groups. DDR transcription profiling further classified tumors into four groups. Those with high DDR transcription across pathways were linked to poor survival independent of IDH or MGMT status, and potentially improved prognostication beyond established biomarkers. Single-cell characterization of a separate cohort revealed intratumoral DDR diversity and identified proliferative tumor cells with high DDR protein expression across pathways that are associated with unfavorable grade and survival.

Conclusions: Tumor-level epigenetic and transcriptional DDR signatures alone can distinguish molecular-defined diagnosis and outcomes of gliomas beyond established biomarkers. A higher abundance of glioma cells with high DDR effector expression across pathways is associated with poor survival. Thus, clinical assessment of pan-DDR expression may inform prognosis and identify potential therapeutic targets.

Background: The 2 most prevalent types of spinal ependymal tumors are myxopapillary ependymomas (MPE) and spinal ependymomas (SP-EPN). Based on molecular data from bulk tumor samples, we previously identified clinically relevant subtypes with poor (MPE-A; SP-EPN-A) and favorable progression-free survival (MPE-B; SP-EPN-B). However, detailed cellular composition, molecular heterogeneity, and features of tumor progression are largely unknown.

Methods: We performed singlenucleus transcriptomic sequencing of 25 formalin-fixed and paraffin-embedded spinal ependymal tumors, including all MPE and SP-EPN subtypes and 6 paired primary and relapsed MPE-A.

Results: Ependymoma subtypes presented with a broad, but comparable tumor microenvironment. Furthermore, neoplastic cells demonstrated inter- and intratumoral heterogeneity regarding cancer cell state composition. Overall, MPE tumors exhibited a significantly higher abundance of the astrocytic state, whereas a ciliated state was more prevalent in SP-EPN. Also, transcriptome-inferred copy number variation (CNV) profiles revealed tumor cell clusters with distinct chromosomal alterations across tumors, suggesting subclonal neoplastic growth. Compared to normal human spinal cord cell populations, MPE tumor cells displayed similarities to astrocytes and ependymal cells, whereas SP-EPN exclusively matched ependymal cells. Myxopapillary ependymomas of type A demonstrated a distinct profile, being similar to the roof and floor plate of the developing spinal cord. Paired primary and relapsed MPE-A revealed mostly similar histology, epigenetics, CNV profiles, and cellular composition of neoplastic cells.

Conclusion: Single-nucleus transcriptomic sequencing provides valuable insights into the molecular composition of spinal ependymoma types and subtypes and may pave the way for a better understanding of tumor evolution and identification of therapeutic targets.

Background: Disruption of the blood-brain barrier (BBB) in high-grade brain tumors is characterized by contrast accumulation on diagnostic imaging. This window of opportunity study correlates contrast imaging features with the tumor distribution of BBB-permeable (levetiracetam) and -impermeable (cefazolin) drugs.

Methods: Patients with a clinical diagnosis of a high-grade brain tumor underwent MRI for surgical planning. Cefazolin and levetiracetam were administered prior to skin incision, and serial plasma and image-registered tumor samples were collected during the operation. Drug levels were measured by LC-MS/MS, tissue drug levels were corrected for residual blood, and tumor-to-plasma concentration ratios were calculated. Intraoperative microdialysis was performed in a subset of patients to measure the same two drugs.

Results: Tumor (n = 125) and plasma (n = 261) samples were available for analysis from 42 operative cases. Across all samples, the tumor-to-plasma ratio was significantly lower for cefazolin (marginal mean [MM]: 0.15, 95% CI: 0.11-0.19) as compared to levetiracetam (MM: 0.70, 95% CI: 0.64-0.75; P < .001). When compared between contrast-enhancing and non-enhancing regions, tumor-to-plasma ratios for cefazolin varied by 4.4-fold (0.27, 95% CI: 0.20-0.35 vs. 0.06, 95% CI: 0.04-0.08, respectively; P < .001), and varied for levetiracetam by 1.4-fold (0.88, 95% CI: 0.78-0.97 vs. 0.61, 95% CI: 0.55-0.66, respectively; P < .001). These results were confirmed with the intra-operative microdialysis and a population pharmacokinetic analysis.

Conclusions: This study demonstrates significant inter- and intra-tumoral heterogeneity in drug delivery for both levetiracetam and cefazolin within high-grade brain tumors that is not necessarily predicted by clinical MR imaging and may reflect tumor-induced changes in both perfusion and BBB integrity.

Background: Craniopharyngioma presents malignant clinical manifestations with severe symptoms and higher incidence of hypothalamic dysfunction. The pathogenesis of craniopharyngioma remains unclear, which impedes the development of effective treatments and preventive measures. Comprehensively understanding the neoplastic programming and tumoral evolution may contribute to the improvement of prognosis for craniopharyngioma.

Methods: Using the single cell RNA-sequencing and high-resolution spatial transcriptomics analysis on adamantinomatous craniopharyngioma (ACP), papillary craniopharyngioma (PCP), and Rathke cleft cyst (RCC) to depict the cellular hierarchies and neoplastic evolution. Multiplex immunohistochemistry and ex vivo pituitary culture from animal model were used to identify the putative therapeutic targets.

Results: Cellular hierarchy analysis uncovered a more inflammatory tumor microenvironment in PCP compared to ACP. Parallel genomic variation and gene expression patterns were revealed between PCP and RCC, suggesting a continuum of the same disease spectrum that evolutes from RCC to PCP. Furthermore, we identified the disease-type-unique structures composed of various cellular states, including the tumoral progenitors surrounding the fibrovascular cores in PCP and senescence associated secretory phenotype (SASP)-related cellular hierarchy in ACP, respectively. In addition, SASP-related fibroblast growth factor (FGF) signaling was identified as a potential therapeutic target for ACP and inhibition of it led to decreased tumor cell proliferation in murine model.

Conclusions: Our study reveals the neoplastic programming and evolution of craniopharyngioma at single cell and spatial levels. Notably, SASP-related FGF signaling is identified as a potential therapeutic target for ACP and inhibition of it reduces tumor cell proliferation in murine model.

Background: Diffuse midline gliomas (DMGs), particularly diffuse intrinsic pontine gliomas (DIPGs), are aggressive pediatric brain tumors with a median survival of less than 12 months. Notably, approximately 70% of these tumors harbor P53 pathway alterations, including TP53 or PPM1D mutations. Identifying precision therapies for this subset is crucial. This study aims to employ transcriptomics-guided high-throughput drug screening to identify effective treatments for DIPG/DMG with P53 pathway alterations.

Methods: Transcriptomic profiling of 98 patient samples containing 31 DIPGs revealed key activated pathways. Patient-derived cell lines were subjected to high-throughput screening using a cell cycle-targeting drug library. Lead candidates were validated both in vitro and in orthotopic xenograft models, while combination therapies were assessed for their ability to overcome TP53-mutant resistance.

Results: Transcriptomic analysis revealed activation of P53 and cell cycle pathways in DIPGs. High-throughput drug screening identified SN-38, a topoisomerase I inhibitor, as selectively targeting TP53 wild-type tumor cells by inducing G2 arrest and apoptosis. TP53 knockdown abolished SN-38's efficacy, while PPM1D knockdown enhanced sensitivity, confirming a TP53-dependent mechanism. Conversely, TP53-mutated cells exhibited SN-38 resistance via ATR pathway activation. Combining SN-38 with the ATR inhibitor AZ20 restored apoptosis and suppressed TP53-mutant tumor growth in vitro and in vivo.

Conclusions: Guided by transcriptomic profiling, this study utilized high-throughput drug screening to identify SN-38 as a potential therapy for TP53 wild-type DIPG/DMG, while the SN-38 and AZ20 combination was effective against TP53-mutant tumors. This approach provides a promising treatment strategy for this malignancy and establishes a novel paradigm for drug screening in DIPG/DMG.