Neuro-oncology advances最新文献

Background: Glioblastoma is the most aggressive malignant brain tumor with poor survival due to its invasive nature driven by cell migration, with unclear linkage to transcriptomic information. The aim of this study was to develop a physics-based framework connecting to transcriptomics to predict patient-specific glioblastoma cell migration.

Methods and results: We applied a physics-based motor-clutch model, a cell migration simulator (CMS), to parameterize the migration of glioblastoma cells and define physical biomarkers on a patient-by-patient basis. We reduced the 11-dimensional parameter space of the CMS into 3 principal physical parameters that govern cell migration: motor number-describing myosin II activity, clutch number-describing adhesion level, and F-actin polymerization rate. Experimentally, we found that glioblastoma patient-derived (xenograft) cell lines across mesenchymal (MES), proneural, and classical subtypes and 2 institutions (N = 13 patients) had optimal motility and traction force on stiffnesses around 9.3 kPa, with otherwise heterogeneous and uncorrelated motility, traction, and F-actin flow. By contrast, with the CMS parameterization, we found that glioblastoma cells consistently had balanced motor/clutch ratios to enable effective migration and that MES cells had higher actin polymerization rates resulting in higher motility. The CMS also predicted differential sensitivity to cytoskeletal drugs between patients. Finally, we identified 18 genes that correlated with the physical parameters, suggesting transcriptomic data alone could potentially predict the mechanics and speed of glioblastoma cell migration.

Conclusions: We describe a general physics-based framework for parameterizing individual glioblastoma patients and connecting to clinical transcriptomic data that can potentially be used to develop patient-specific anti-migratory therapeutic strategies.

Background: Gliomas, the most frequent malignant primary brain tumors, lack curative treatments. Understanding glioma-specific molecular alterations is crucial to develop novel therapies. Among them, the biological consequences of the isocitrate dehydrogenase 1 gene mutation (IDH1 ^R132H) remain inconclusive despite its early occurrence and widespread expression.

Methods: We thus employed CRISPR/Cas adenine base editors, which allow precise base pair alterations with minimal undesirable effects, to correct the IDH1 ^R132H mutation.

Results: Successful correction of the IDH1 ^R132H mutation in primary patient-derived cell models led to reduced IDH1 ^R132H protein levels and decreased production of 2-hydroxyglutarate, but increased proliferation. A dual adeno-associated virus split intein system was used to successfully deliver the base editor in vitro and in vivo.

Conclusions: Taken together, our study provides a strategy for a precise genetic intervention to target the IDH1 ^R132H mutation, enabling the development of accurate models to study its impact on glioma biology and serving as a framework for an in vivo gene therapy.

Background: Biological sex is an important risk factor for glioblastoma (GBM), with males having a higher incidence and poorer prognosis. The mechanisms for this sex bias are thought to be both tumor intrinsic and tumor extrinsic. MicroRNAs (miRNAs), key posttranscriptional regulators of gene expression, have been previously linked to sex differences in various cell types and diseases, but their role in the sex bias of GBM remains unknown.

Methods: We leveraged previously published paired miRNA and mRNA sequencing of 39 GBM patients (22 male, 17 female) to identify sex-biased miRNAs. We further interrogated a separate single-cell RNA-sequencing dataset of 110 GBM patients to examine whether differences in miRNA target gene expression were tumor cell-intrinsic or tumor cell extrinsic. Results were validated in a panel of patient-derived cell models.

Results: We identified 10 sex-biased miRNAs (p _adjusted < .1), of which 3 were more highly expressed in males and 7 more highly expressed in females. Of these, miR-644a was higher in females, and increased expression of miR-644a target genes was significantly associated with decreased overall survival (HR 1.3, P = .02). Furthermore, analysis of an independent single-cell RNA-sequencing dataset confirmed sex-specific expression of miR-644a target genes in tumor cells (P < 10^-15). Among patient-derived models, miR-644a was expressed a median of 4.8-fold higher in females compared to males.

Conclusions: Our findings implicate miR-644a as a candidate tumor cell-intrinsic regulator of sex-biased gene expression in GBM.

Background: Depression is common among glioma patients, and antidepressants are frequently prescribed to manage symptoms. Understanding the impact of antidepressants on glioma patient survival is crucial for informing treatment strategies.

Methods: A systematic search was conducted in PubMed and EMBASE databases for studies published from January 1994 to March 2024. The search strategy included terms related to overall survival, prognosis, antidepressants, and gliomas. A manual search was performed in the reference lists. According to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guideline, 2 authors independently extracted data. Statistical analysis was performed using Review Manager (version 5.4.1) software, employing a random effects model based on study heterogeneity. The primary outcome was overall survival (OS). Hazard ratios (HRs) were used to present survival differences between the 2 arms. HRs after correcting for confounders were prioritized for extraction.

Results: Seven retrospective cohort studies involving 5579 patients were analyzed. Selective serotonin reuptake inhibitors (SSRIs) showed no significant survival difference in all glioma patients (HR = 1.34, 95% confidence interval [CI]: 0.66-2.70) and in GBM patients (HR = 1.05, 95% CI: 0.45-2.46), while non-SSRIs had an unfavorable impact on OS in GBMs (HR = 3.54, 95% CI: 2.51-4.99). When considering LGG, both SSRIs and non-SSRIs usage demonstrated associations with poorer survival outcomes (SSRIs: HR = 3.26, 95%CI: 2.19-4.85; Non-SSRIs: HR = 7.71, 95% CI: 4.25-14.00).

Conclusions: Antidepressant use was not significantly associated with better survival outcomes, emphasizing the need for reconsidering the real effects of antidepressant medication. Future clinical research should address patient heterogeneity to better clarify the effects of antidepressants on glioma survival.

Background: In the present study, early response assessment by o-(2-[¹⁸F]fluoroethyl)-l-tyrosine (FET) positron emission tomography (PET) and contrast-enhanced magnetic resonance imaging (MRI) were investigated in a phase II open-label single-center study of nivolumab plus bevacizumab for recurrent high-grade astrocytic glioma.

Methods: Twenty patients with nonresectable first recurrence of high-grade astrocytic glioma after EORTC/NCIC protocol underwent [¹⁸F]FET PET/MRI at baseline and after 2 cycles of treatment. Whole brain values of contrast-enhancing volume on MRI (CEV), of the mean (TBR_mean) and maximal tumor-to-background ratio (TBR_max), and of metabolically active volume (MTV) on [¹⁸F]FET PET were obtained. Regional changes in [¹⁸F]FET uptake were assessed by parametric response mapping (PRM). Prediction of overall survival (OS) and response (OS > 11 months) were assessed by Cox and receiver operating characteristic (ROC) analysis, respectively. Also, MRI (response assessment in neuro-oncology [RANO] 2.0) and PET-based (PET RANO 1.0) response assessment criteria were compared.

Results: In ROC analysis responders were separated (P < .05) from nonresponders by lower MTV at follow-up (AUC 0.771, cutoff 18.3 mL), larger decrease in MTV (AUC 0.757, cutoff -5.3 mL), larger decrease in both TBR_max (AUC 0.814, cutoff -0.53) and relative TBR_max (AUC 0.829, cutoff -11%) and smaller PRM progressive volume (AUC 0.843, cutoff 4.0 mL). Change in CEV did not predict response. RANO 2.0 and PET RANO response assessment criteria had similar and only borderline prognostic values.

Conclusions: The study indicates that [¹⁸F]FET PET is superior to contrast-enhanced MRI for early response assessment in patients with recurrent high-grade astrocytic glioma treated with nivolumab and bevacizumab.

Background: Brain tumor needle biopsy interventions are inflicted with nondiagnostic or biased sampling in up to 25% and hemorrhage, including asymptomatic cases, in up to 60%. To identify diagnostic tissue and sites with increased microcirculation, intraoperative optical techniques have been suggested. The aim of this study was to investigate the clinical implications of in situ optical guidance in frameless navigated tumor biopsies.

Methods: Real-time feedback on protoporphyrin IX (PpIX) fluorescence, microcirculation, and gray-whiteness was given before tissue sampling (272 positions) in 20 patients along 21 trajectories in total. The primary variables of investigation were fluorescence in relation to neuropathological findings and gadolinium (Gd) enhancement, increased cerebral microcirculation in relation to bleeding incidence, number of trajectories, and impact on operation time.

Results: PpIX fluorescence was detected in Glioblastoma IDH-wildtype CNS WHO grade 4 (n = 12), Primary diffuse large B-cell lymphoma (n = 3), astrocytoma IDH-mutated CNS WHO grade 4 (n = 1) (Ki67 indices ≥ 15%). For 2 patients, no PpIX fluorescence or Gd was found, although samples contained tumorous tissue (Ki67 index 6%). Increased microcirculation was found along 9 trajectories (34 sites), located in cortical, tumorous, or tentorium regions. Postoperative bleedings (n = 10, nine asymptomatic) were related to skull opening or tissue sampling. This study strengthens the proposed independence from intraoperative neuropathology as PpIX fluorescence is detected. Objective real-time feedback resulted in fewer trajectories compared to previous studies indicating reduced operation time.

Conclusions: The integrated optical guidance system provides real-time feedback in situ, increasing certainty and precision of diagnostic tissue before sampling during frameless brain tumor biopsies.

Background: Ependymomas of the spinal cord are rare among children and adolescents, and the individual risk of disease progression is difficult to predict. This study aims to evaluate the prognostic impact of molecular typing on pediatric spinal cord ependymomas.

Methods: Eighty-three patients with spinal ependymomas ≤22 years registered in the HIT-MED database (German brain tumor registry for children, adolescents, and adults with medulloblastoma, ependymoma, pineoblastoma, and CNS-primitive neuroectodermal tumors) between 1992 and 2022 were included. Forty-seven tumors were analyzed by DNA methylation array profiling. In 6 cases, HOXB13 and MYCN proteins were detected as surrogate markers for specific methylation classes. Ten patients had NF2-related schwannomatosis.

Results: With a median follow-up time of 4.9 years, 5- and 10-year overall survival (OS) were 100% and 86%, while 5- and 10-year progression-free survival (PFS) were 65% and 54%. Myxopapillary ependymoma (SP-MPE, n = 32, 63%) was the most common molecular type followed by spinal ependymoma (SP-EPN, n = 17, 33%) and MYCN-amplified ependymoma (n = 2, 4%). One case could not be molecularly classified, and one was reclassified as anaplastic pilocytic astrocytoma. 5-year PFS did not significantly differ between SP-MPE and SP-EPN (65% vs. 78%, P = .64). MYCN-amplification was associated with early relapses (<2.3 years) in both cases and death in one patient. Patients with SP-MPE subtype B (n = 9) showed a non-significant trend for better 5 years-PFS compared to subtype A (n = 18; 86% vs. 56%, P = .15). The extent of resection and WHO tumor grades significantly influenced PFS in a uni- and multivariate analysis.

Conclusions: Molecular typing of pediatric spinal ependymomas aids in identifying very high-risk MYCN-amplified ependymomas. Further insights into the molecular heterogeneity of spinal ependymomas are needed for future clinical decision-making.

Background: Glioblastoma (GB) is known for its highly invasive nature. Images of butterfly GB (bGB) often illustrate this characteristic, but the molecular background and origins of bGB remain unknown.

Methods: We analyzed a cohort of 34 bGB patients from our dataset (K-cohort) and 46 bGB patients from publicly available datasets, including TCGA-GBM, CPTAC-GBM, IvyGAP, and UPENN-GBM.

Results: In the K-cohort, the median age was 66 years, and molecular analyses revealed TERT promoter mutations in 55.9% of cases, with no cases exhibiting H3F3A, HIST1H3B, or BRAF mutations. Sequential radiological imaging from the K-cohort provided unique insights, showing one case originating in the corpus callosum (CC) and 3 cases originating in the cerebral hemisphere before developing into bGB. Multi-regional sampling supported a mutational trajectory from the hemisphere to the CC. These observations indicate the presence of 2 distinct radiological origins for bGB. Consequently, we classified cases into CC-type and Hemispheric-type based on the tumor volume ratio within the CC. This subgrouping was clinically meaningful; the CC-type is an independent poor prognostic factor for overall survival, with a hazard ratio of 1.8 (95% confidence interval 1.1-3.0, P = .033), and is molecularly distinct by a higher frequency of methylated MGMTp (P = .0039) compared to the Hemispheric-type.

Conclusions: Our results highlight that the radiological features of bGB are not homogenous and can indicate 2 potential subtypes based on their origins. Further studies are mandatory, but CC-type and Hemispheric-type exhibit distinct clinical backgrounds, outcomes, and molecular features.

Background: Neurofibromatosis type 1 (NF1) is a common genetic disorder of phenotypic variability with age-dependent penetrance. This study describes the diagnosis, clinical characterization, management, and outcomes of a large patient cohort with plexiform neurofibroma (PN) treated with selumetinib in a real-world clinical setting.

Methods: This single-center observational study consecutively enrolled patients with NF1-PN treated with selumetinib from April 2018 to 2023. Data on clinical features, tumor types and locations, and results from genetic tests were recorded at baseline; details of disease management with selumetinib and surgical intervention and disease evolution including imaging data and evaluations of pain and function were documented.

Results: Overall, 54 patients with a median age (range) of 16.4 (4.5-58.0) years were enrolled. Most had cutaneous manifestations (88.9%), including cutaneous neurofibromas and PN. Patients underwent [18F]fluorodeoxyglucose (FDG)-PET/CT imaging before treatment to rule out malignant lesions. Initial evaluations included directed magnetic resonance imaging (MRI), which facilitated future comparisons and allowed for the assessment of PN resectability. Pharmacological treatment with selumetinib (with surgery, without surgery) resulted in the following proportion of patients achieving stable disease (58.8%, 54.3%), partial response (29.4%, 28.6%), and improved pain (58.8%, 37.1%), deformity (17.6%, 20.0%), and functional (17.6%, 20.0%) outcomes, respectively.

Conclusions: Results from this study demonstrate that NF1-PN can be managed effectively with selumetinib with surgical intervention in some patients. Most patients achieved tumor stability and improved symptom control, and the majority of patients continue under treatment. Effective diagnosis and management were achieved through individualized utility of FDG-PET/CT and MRI imaging and targeted resource allocation.