Neuro-oncology advances最新文献

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.

Background: Non-small-cell lung cancer (NSCLC) is associated with a high incidence of brain metastasis (BM), and the prognosis of patients with NSCLC and BM is poor. This study aimed to identify the prognostic factors and elucidate the survival rates of Japanese patients with NSCLC and BM at initial diagnosis.

Methods: HOT 1701 is a retrospective multicenter study of patients with NSCLC and BM at initial diagnosis. The medical records of all consecutive patients diagnosed with advanced or recurrent NSCLC and BM at 14 institutions of the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) in Japan were reviewed. The participants were categorized based on the presence or absence of driver mutations. The Kaplan-Meier method was used to estimate median overall survival (OS). Univariate and multivariate analyses were performed to identify prognostic factors in these patients.

Results: Among 566 patients with NSCLC and BM, the median OS was 11.8 months. Patients with driver mutations survived longer than those without driver mutations. The univariate and multivariate analyses revealed 6 independent prognostic factors: age ≥65 years, poor performance status, T factor, absence of driver gene mutations, presence of extracranial metastases, and number of BM. According to the prognostic score based on these 6 factors, the patients were stratified into 3 risk groups: low-, intermediate-, and high-risk, with median OS of 27.8, 12.2, and 2.8 months, respectively.

Conclusions: We developed a new prognostic model for patients with NSCLC and BM, which may help determine prognosis at diagnosis.

Background: Medulloblastoma (MB) is the most common high-grade pediatric brain tumor, comprised of 4 main molecular subgroups-sonic-hedgehog (SHH), Wnt, Group 3, and Group 4. Group 3 and Group 4 tumors are the least characterized MB subgroups, despite Group 3 having the worst prognosis (~50% survival rate), and Group 4 being the most prevalent. Such poor characterization can be attributed to high levels of inter- and intratumoral heterogeneity, making it difficult to identify common therapeutic targets.

Methods: In this study, we generated single-cell sequencing data from 14 MB patients spanning all subgroups that we complemented with publicly available single-cell data from Group 3 patients. We used a ligand-receptor analysis tool (CellChat), expression- and allele-based copy-number variation (CNV) detection methods, and RNA velocity analysis to characterize tumor cell-cell interactions, established a connection between CNVs and temporal tumor progression, and unraveled tumor evolution.

Results: We show that MB tumor cells follow a temporal trajectory from those with low CNV levels to those with high CNV levels, allowing us to identify early and late markers for SHH, Group 3, and Group 4 MBs. Our study also identifies SOX4 upregulation as a major event in later tumor clones for Group 3 and Group 4 MBs, suggesting it as a potential therapeutic target for both subgroups.

Conclusion: Taken together, our findings highlight MB's inherent tumor heterogeneity and offer promising insights into potential drivers of MB tumor evolution particularly in Group 3 and Group 4 MBs.

Background: High-grade gliomas (HGGs) are the most aggressive type of gliomas and have the poorest outcomes. Chromatin remodeling (CR) genes have been implicated in multiple oncogenic pathways in numerous cancer types. In gliomagenesis, CR genes have been implicated in regulating the stemness of glioma cells, the tumor microenvironment (TME), and resistance to therapies.

Methods: We performed molecular profiling of 4244 HGGs and evaluated associations of CR mutations with other cancer-related biomarkers, infiltration by immune cells, and immune gene expression. We also evaluated the association between CR mutations and survival in wild-type IDH HGG patients.

Results: Nearly 10% of HGGs carry mutations in CR genes, with a higher prevalence (15%) in HGGs with IDH mutations. Analysis of cooccurrence with other biomarkers revealed that CR-mutated HGGs possess favorable genetic alterations which may have prognostic value. CR-mutated HGGs with wild-type IDH demonstrated colder TME and worse OS overall compared to the CR-wild-type HGGs.

Conclusions: Our study reveals the prognostic effects of CR mutations in HGG and points to several biomarker candidates that could suggest sensitivity to emerging therapeutic strategies.