Neuro-oncology advances最新文献

Background: Array-based DNA methylation profiling is the gold standard for central nervous system (CNS) tumor molecular classification, but requires over 100 ng input DNA from surgical tissue. Cell-free tumor DNA (cfDNA) in cerebrospinal fluid (CSF) offers an alternative for diagnosis and disease monitoring. This study aimed to test the utilization of enzymatic DNA methylation sequencing (EM-seq) methods to overcome input DNA limitations.

Methods: We used the NEBNext EM-seq v2 kit on various amounts of cfDNA, as low as 0.1 ng, extracted from archival CSF samples of 10 patients with CNS tumors. Tumor classification was performed via MNP-Flex using CpG sites overlapping those on the MethylationEPIC array.

Results: EM-seq provided sufficient genomic coverage for 10 and 1 ng input DNA samples to generate global DNA methylation profiles. Samples with 0.1 ng input showed lower coverage due to read duplication. Methylation levels for CpG sites with at least 5× coverage were highly correlated across various input DNA amounts, indicating that lower input cfDNA can still be used for tumor classification. The MNP-Flex classifier, trained on tissue DNA methylation data, successfully predicted CNS tumor types for 7 out of 10 CSF samples using EM-seq methylation data with only 1 ng of input cfDNA, consistent with diagnoses based on tissue MethylationEPIC classification and/or histopathology. Additionally, we detected focal and arm-level copy number alterations previously identified via clinical cytogenetics of tumor tissue.

Conclusions: This study demonstrated the feasibility of CNS tumor molecular classification based on CSF using the EM-seq approach, and establishes potential sample quality limitations for future studies.

Background: Differentiating tumor progression from posttreatment changes, such as pseudoprogression and radiation necrosis, remains a significant challenge in neuro-oncology. Contrast Clearance Analysis (CCA), or Treatment Response Assessment Maps, has developed as a promising tool for this purpose. This systematic review and meta-analysis evaluate the diagnostic accuracy of CCA in distinguishing tumor progression from treatment-induced changes and compare its performance with other advanced imaging modalities.

Methods: Following PRISMA-DTA guidelines, a comprehensive search was conducted across PubMed, Scopus, Web of Science, and Embase up to May 2025. Quality assessment was performed using the QUADAS-2 tool. Diagnostic accuracy metrics, including sensitivity, specificity, and area under the curve (AUC), were pooled using a bivariate random-effects meta-analysis model.

Results: Nine studies involving 240 patients and 407 brain lesions were included. Contrast Clearance Analysis demonstrated a pooled sensitivity of 91% (95% CI, 0.84-0.95), a specificity of 92% (95% CI, 0.87-0.95), and an AUC of 88%. Moderate heterogeneity was observed in specificity (I² = 37.3%), with no significant heterogeneity in sensitivity (I² = 0%). Publication bias was detected (P <.001), with the trim-and-fill method suggesting 5 potentially missing studies. Quality assessment revealed a considerable risk of bias in the reference test domain.

Conclusion: Contrast Clearance Analysis demonstrates high diagnostic accuracy in differentiating tumor progression from posttreatment changes, outperforming conventional MRI and showing comparable or superior performance to other advanced imaging techniques such as MR perfusion, diffusion-weighted imaging, and MR spectroscopy. However, methodological limitations and variability in reference standards highlight the need for standardized protocols in future research.

Background: Diffuse intrinsic pontine glioma (DIPG) carries a high mortality rate and lacks effective treatment options with a median overall survival (OS) of 8-12 months. Convection-enhanced delivery (CED) has demonstrated safety in phase I trials, but efficacy is indeterminate. Evaluating anatomic patterns of relapse may aid in determining therapeutic efficacy of local CED drug delivery strategies.

Methods: Sixty-three children with DIPG were retrospectively reviewed for first radiographic progression. All patients were treated using conventional external beam radiation (EBRT) and 31 were treated with CED of radiolabeled 124-iodine-omburtamab (NCT01502917). Anatomic patterns of initial progression were coded by independent neuroradiologists. OS and cumulative incidence of progression at each anatomic site were assessed in a competing risk analysis with death as a competing variable and were stratified based on CED treatment.

Results: Median OS was 14.67 months for the cohort. Patients receiving CED demonstrated higher rates of progression in general, when considering progression at all anatomical sites (HR 1.79, P = .047); no significant difference was found in OS when stratified by CED treatment (P = .22). However, CED treatment was associated with significantly lower cumulative incidence of local pontine and medullary progression (HR: 0.42, P = .03; HR 0.14, P = .01, respectively) relative to non-CED-treated patients.

Conclusions: Anatomically defined patterns of relapse provide evidence for locoregional control in children with DIPG treated with radioimmunotherapy administered by CED. Future CED or local surgical therapy trials can benefit from including detailed patterns of relapse as a prospective outcome.

Background: High-grade glioma (HGG) is an aggressive tumor for which there are no effective therapies at recurrence, especially for isocitrate dehydrogenase (IDH)-wild-type glioblastoma. This retrospective study compared survival outcomes between patients receiving bevacizumab alternating chemotherapy (BAC) and those receiving bevacizumab (BEV) alone.

Methods: We collected data from 95 adult patients with rHGG who were treated at our institute between January 2018 and August 2023. The patients were divided into 3 groups based on treatment and glioma grade: BAC regimen to treat grade 3 gliomas (n = 23), BAC regimen to treat grade 4 gliomas (n = 29), and treatment with BEV alone (n = 43). The BAC regimen included 2 cycles of etoposide + carboplatin, followed by 1 cycle of cyclophosphamide + vinblastine, with bevacizumab (10 mg/kg) every 4 weeks. One full cycle lasted approximately 3 months. We analyzed overall survival (OS) and postrecurrence survival (PRS).

Results: In patients with grade 4 gliomas, the BAC regimen significantly improved survival compared with BEV alone, with a median OS of 29 versus 19 months and a PRS of 16 versus 10 months (both P < .05). In the IDH-wild-type subgroup, the BAC regimen produced a median OS of 27 versus 19 months and a PRS of 16 versus 10 months (P < .05). The 2-year OS and PRS rates were also higher in the BAC groups. Notably, patients with MGMT-methylated grade 4 gliomas treated with the BAC regimen had the longest median OS, 33 months.

Conclusions: The BAC regimen appears effective and well tolerated in adult patients with rHGG, particularly in younger patients. Its alternating design may improve the median OS (29 vs. 19 months) and PRS (16 vs. 10 months) of patients with grade 4 gliomas while maintaining safety. As a practical option for those ineligible for clinical trials, BAC warrants further evaluation in prospective randomized studies to confirm its benefits and address the limitations of retrospective analysis.

Background: This first-in-human study evaluated EGFRvIII × CD3 TCB, a novel T cell bispecific antibody, in patients with newly diagnosed EGFRvIII-positive glioblastoma.

Methods: Patients with newly diagnosed glioblastoma received escalating doses of EGFRvIII × CD3 TCB following chemoradiation. The primary objectives were to evaluate safety/tolerability and define the maximum tolerated dose (MTD); secondary objectives included pharmacokinetics (PK), immunogenicity, pharmacodynamics, and clinical activity.

Results: Thirty-six patients were enrolled, 32 with unmethylated and 4 with methylated MGMT promoter. EGFRvIII × CD3 TCB doses ranged from 0.004 to 10 mg Q3W, administered either on a flat or step-up dose schedule. One DLT occurred (grade 3 seizure). The MTD was not reached. Most adverse events (AEs) were of grade 1-2 severity, with headache being the most common treatment-related AE (22%). EGFRvIII × CD3 TCB showed dose-proportional PK in serum and cerebrospinal fluid (CSF), with a CSF/serum ratio of 0.08. At the highest dose tested, 10 mg Q3W, maximum serum concentrations remained 6-fold below the lower boundary of the predicted anticipated therapeutic dose.

Conclusions: The administration of EGFRvIII × CD3 TCB in a maintenance setting, following standard of care treatment, was safe and well tolerated up to the highest tested dose of 10 mg Q3W. However, evidence of efficacy was not observed at the evaluated doses, suggesting that a study of higher dose levels may be warranted.

Background: Emerging evidence suggests that cognitive dysfunction may result from damage to the brain's functional network. This study explores the dose-dependent susceptibility of functional hubs to radiotherapy (RT) and associations with cognitive outcomes.

Methods: Attention, language, memory, motor, and executive functioning were assessed ≥1-year post-radiotherapy in 39 WHO grade 2 or 3 glioma patients with lesions predominantly located in the left frontal lobe and 50 matched healthy controls. Using resting-state functional imaging, weighted functional graphs were constructed for each participant, identifying hubs through graph measures. Linear regression models and Spearman's rho correlations assessed associations between mean RT dose per region and cognitive domains.

Results: Higher RT doses to the left fusiform and inferior temporal gyri were linked to memory impairment (r(37) ≥ -0.565, P _FDR ≤ 0.026), while poorer language outcomes were associated with higher doses to the left pars opercularis, rostral middle frontal gyrus, and caudate (r(37) ≥ -0.510, P _FDR ≤ .040). Attention deficits were linked to higher doses to the left posterior cingulate, precentral, supramarginal, and postcentral gyrus ((37) ≥ -0.499, P _FDR ≤ .040), with the left postcentral gyrus also associated with executive dysfunction (r(37) = -0.526, P _FDR = .029). Significant correlations between RT dose and cognitive outcomes were more frequent in hubs than in non-hubs (50% vs. 12%, P = .005) and exclusively found in left-sided regions.

Conclusions: RT seems to adversely affect left-sided functional hubs in a dose-dependent manner in glioma patients, which may contribute to cognitive dysfunction. Protecting these regions from the dose may potentially mitigate cognitive side effects in glioma patients. However, since most lesions were located in the left hemisphere and baseline testing was unavailable, a potential effect of tumor location cannot be entirely ruled out.

Background: Glucocorticoids (GCs) play a crucial therapeutic role in managing cerebral edema caused by radiation-induced acute brain injury or brain metastases. However, they negatively impact the efficacy of immunotherapy.

Methods: We collected data from 62 patients with non-small cell lung cancer (NSCLC) brain metastases who received immunotherapy combined with intracranial radiotherapy within 28 days of each other. The overall doses of GCs for each patient were expressed as the cumulative total dose of dexamethasone equivalents during the baseline period of immunotherapy. These patients were categorized based on their baseline GCs usage (28 days before and after the first immunotherapy) into three groups: low GCs use (< 30 mg), medium GCs use (30-100 mg), and high GCs use (≥ 100 mg).

Results: Among the three groups of included patients in our study, the median intracranial progression-free survival (iPFS) was significantly shorter in the high GCs use group compared to the medium and low GCs use groups (5.23 months vs. 12.70 months vs. 16.43 months, P < .001). No significant difference in median iPFS was observed between the medium and low GCs use groups. Median overall survival (OS) and median progression-free survival (PFS) among the three groups had a similar trend with iPFS. No significant differences in intracranial objective response rate (iORR) and objective response rate (ORR) were found among the three groups. Standard propensity score matching (PSM) confirmed that the high GCs use group (≥ 100 mg) still had significantly shorter median iPFS, PFS, and OS compared to the other groups.

Conclusions: Increased baseline GCs use is associated with reduced efficacy of the combination therapy in these patients and baseline high-dose GCs use (≥ 100 mg) notably impairs survival outcomes.

Background: Although the differential prognostic value of 1D, 2D, and volumetric meningioma size assessment has been reported, RANO meningioma criteria rely on bidimensional measurements.

Methods: In this post-hoc analysis of the EORTC-BTG 1320 trial, contrast-enhancing CNS WHO grade 2 and 3 meningiomas were assessed using 1D, 2D, and volumetric measurements. Different cutoff values for lesion size increase were compared 6 months after the start of antineoplastic treatment using Cox proportional hazards models to evaluate their association with overall survival (OS). Optimal cutoff values were identified using two criteria: maximal hazard ratio (HR) for death with statistical significance for median OS and the cutoff that maximized mean specificity and sensitivity for predicting 1-year OS.

Results: Among 57 evaluable patients, unidimensional 5 mm and 10 mm tumor size increase yielded the maximal HRs (HR = 3.41, 95% Confidence Interval (CI) 1.56-7.45, P < .01 and HR = 3.22, 95% CI 1.58-6.58, P < .01, respectively) for OS. A 6 mm tumor size increase maximized mean specificity and sensitivity (HR = 2.91, 95% CI 1.43-5.93, P < .01) for predicting 1-year OS. For tumor volume assessments, a 30% increase was associated with the maximal HR (HR = 3.69, 95% CI 1.64-8.31, P < .01) for OS whereas a 40% increase maximized the mean specificity and sensitivity (HR = 3.66, 95% CI 1.75-7.654, P < .01). Bidimensional measurements showed no significant OS association.

Conclusion: Unidimensional tumor measurements and tumor volume assessments show a stronger association with overall survival than bidimensional measurements in recurrent non-benign meningiomas. Integration of these methods into response assessment criteria for meningiomas should be considered.

Background: Glioblastoma is a rare primary tumor of the brain. Infiltration of glioblastoma into the brain parenchyma may influence prognosis. We therefore aimed to investigate possible influences of distinct patterns of MRI-defined infiltration on the prognosis.

Methods: We performed a retrospective analysis of sequential patients with glioblastoma between April 2005 and December 2017. Patient data were collected from the hospital data management system, MRI images from the hospital PACS and from cooperative radiology units. Patients were divided into subgroups based on the tumor growth pattern (frame-like, palisade-like, infilling). The impact of various factors on overall survival and progression-free survival was then calculated and compared between the groups.

Results: 259 patients were included. Of the 258 evaluable patients, 117 showed a palisade-like infiltration, 98 were classified as non-infiltrating frame-like, and 43 as infilling dense-solid. Standard prognostic factors aligned to published data. In multivariate analysis, no significant influence of palisade-like growth on overall survival and progression-free survival could be detected. In Cox regression analyses, we found a significant effect for overall survival in palisade-like tumors in the univariate analysis (OR 1.354, 95% CI 1.032-1.776, P = .029).

Conclusion: We show here a possible correlation of MRI-based infiltration patterns and survival in patients with glioblastoma. Our results correspond well to published literature that shows that certain subtypes of glioblastoma exhibit an enhanced invasion pattern and decreased survival. Our results should be verified in a prospective setting in a large patient cohort and by using automated methods for the classification of infiltration patterns in glioblastoma.

This review explores innovative therapeutic strategies for treating central nervous system (CNS) tumors by targeting their unique metabolic dependencies. This approach marks a significant departure from traditional cytotoxic treatments, focusing instead on the metabolic vulnerabilities created by the tumor's microenvironment and genetic profile. A key area of interest is the de novo pyrimidine synthesis pathway, which is crucial for DNA and RNA synthesis, DNA repair, and protein glycosylation. We highlight the potential of dihydroorotate dehydrogenase (DHODH) inhibitors, which have shown promising anti-tumor activity in preclinical models. The blood-brain barrier, while a challenge for drug delivery, may enhance the efficacy of these inhibitors by maintaining a unique metabolic environment in the brain. Specific brain tumors, such as glioblastoma multiforme, MYC-amplified medulloblastoma, and IDH mutant gliomas, exhibit heightened sensitivity to DHODH inhibition. We suggest that the unique metabolic environment of the brain could make DHODH a more effective therapeutic target for brain tumors compared to other cancer types. Despite the speculative nature of these findings, the compelling preclinical data warrant further investigation into brain-penetrant DHODH inhibitors for CNS malignancies.