Journal of Neuro-Oncology最新文献

Purpose: We assess the efficacy of different surgical resection types, radiotherapy, systemic therapy on overall survival in very elderly patients (age > 80) with intracranial atypical meningioma in contrast with their elderly (65-80) counterparts.

Methods: Patients > 65 years old with intracranial atypical meningiomas surgically resected and catalogued via the National Cancer Database were included. Cox proportional hazards models were developed to assess the association between surgical resection type, radiotherapy and systemic therapy with OS while controlling for sex, race, ethnicity, facility type, income, tumor size and CDCC score.

Results: 1747 elderly patients and 382 very elderly patients were included. 61.70% elderly patients and 58.90% very elderly patients received GTR. 26.50% elderly patients and 14.13% very elderly patients received radiotherapy. In multivariate analysis, subtotal resection is associated with worse survival (HR 1.28, p < 0.01) and radiotherapy is associated with improved survival (HR 0.76, p < 0.01). Systemic therapy was not associated with changes in survival outcomes (HR 1.17, p = 0.79). Using subgroup analysis, gross total resection is associated with better survival outcomes in both elderly and very elderly cohorts. Radiotherapy was not associated with improved survival (HR 0.85, p = 0.11) for patients between 65 and 80 years old, but was associated with improved survival (HR 0.51, p < 0.01) for patients > 80 years old.

Conclusion: GTR provides survival advantage in both elderly and very elderly cohorts. Radiotherapy provides survival benefits for very elderly patients even though very elderly patients are less likely to received radiotherapy. Very elderly patients may benefit from more aggressive management in the treatment of atypical meningiomas.

Glioblastoma (GBM), the most common and aggressive primary central nervous system (CNS) tumor in adults, continues to have a dismal prognosis. Across hundreds of clinical trials, few novel approaches have translated to clinical practice while survival has improved by only a few months over the past three decades. Randomized controlled trials of immune checkpoint inhibitors (ICIs), which have seen impressive success for advanced or metastatic extracranial solid tumors, have so far failed to demonstrate a clinical benefit for patients with GBM. This has been secondary to GBM heterogeneity, the unique immunosuppressive CNS microenvironment, immune-evasive strategies by cancer cells, and the rapid evolution of tumor on therapy. This review aims to summarize findings from major clinical trials of ICIs for GBM, review historic failures, and describe currently promising avenues of investigation. We explore the biological mechanisms driving ICI responses, focusing on the role of the tumor microenvironment, immune evasion, and molecular biomarkers. Beyond conventional monotherapy approaches targeting PD-1, PD-L1, CTLA-4, we describe emerging approaches for GBM, such as dual-agent ICIs, and combination of ICIs with oncolytic virotherapy, antigenic peptide vaccines, chimeric antigenic receptor (CAR) T-cell therapy, along with nanoparticle-based delivery systems to enhance ICI efficacy. We highlight potential strategies for improving patient selection and treatment personalization, along with real-time, longitudinal monitoring of therapeutic responses through advanced imaging and liquid biopsy techniques. Integrated radiomics, tissue, and plasma-based analyses, may potentially uncover immunotherapeutic response signatures, enabling early, adaptive therapeutic adjustments. By specifically targeting current therapeutic challenges, outcomes for GBM patients may potentially be improved.

Introduction: Spinal low-grade gliomas (sLGGs) are a group of tumors that arise from glial cells in the spinal cord. Current evidence supporting the use of adjuvant radiotherapy for the management of sLGG is lacking. We hence aimed to compare overall survival rates in patients receiving surgery alone with those receiving surgery with adjuvant radiotherapy.

Methods: The NCDB, a large, nationwide, US-based cancer registry was used. Relevant cases were identified using the following ICD-O-3 histological codes: 9382, 9384, 9400, 9410, 9411, 9420, 9421, 9424, 9425, and 9450, along with the ICD-O-3 topographical codes for spinal meninges (C70.1) and spinal cord (C72.0), excluding spinal ependymomas. Overall survival was the primary outcome. Propensity score matching 1:1 was used to balance the cohorts prior to Kaplan-Meier survival analysis.

Results: A total of 552 patients were included in the study, with 440 in the surgery alone group and 156 in the surgery with adjuvant radiotherapy group. Patients in the surgery with adjuvant radiotherapy group were significantly older (median age 40.0 vs. 24.0 years, p < 0.001), and exhibited higher proportions of WHO grade 2 tumors (p < 0.001). Adjuvant chemotherapy was more frequently administered in the surgery with adjuvant radiotherapy group (23% vs. 7%, p < 0.001). Overall, adjuvant radiotherapy was not associated with improved survival, with a significantly higher mortality in the radiotherapy group before propensity score matching (p < 0.0001). After matching, the difference in overall survival was no longer significant (p = 0.11).

Conclusion: This study found no significant overall survival benefit associated with the use of adjuvant radiotherapy for spinal low-grade gliomas (sLGG). Although patients who received adjuvant radiotherapy initially demonstrated higher mortality rates, this difference was largely due to confounding factors such as more advanced disease in this group.

Purpose: Lower-grade gliomas typically exhibit 5-aminolevulinic acid (5-ALA)-induced fluorescence in only 20-30% of cases, a rate that can be increased by doubling the administered dose of 5-ALA. Fluorescence can depict anaplastic foci, which can be precisely sampled to avoid undergrading. We aimed to analyze whether a deep learning model could predict intraoperative fluorescence based on preoperative magnetic resonance imaging (MRI).

Methods: We evaluated a cohort of 163 glioma patients categorized intraoperatively as fluorescent (n = 83) or non-fluorescent (n = 80). The preoperative MR images of gliomas lacking high-grade characteristics (e.g., necrosis or irregular ring contrast-enhancement) consisted of T1, T1-post gadolinium, and FLAIR sequences. The preprocessed MRIs were fed into an encoder-decoder convolutional neural network (U-Net), pre-trained for tumor segmentation using those three MRI sequences. We used the outputs of the bottleneck layer of the U-Net in the Variational Autoencoder (VAE) as features for classification. We identified and utilized the most effective features in a Random Forest classifier using the principal component analysis (PCA) and the partial least square discriminant analysis (PLS-DA) algorithms. We evaluated the performance of the classifier using a tenfold cross-validation procedure.

Results: Our proposed approach's performance was assessed using mean balanced accuracy, mean sensitivity, and mean specificity. The optimal results were obtained by employing top-performing features selected by PCA, resulting in a mean balanced accuracy of 80% and mean sensitivity and specificity of 84% and 76%, respectively.

Conclusions: Our findings highlight the potential of a U-Net model, coupled with a Random Forest classifier, for pre-operative prediction of intraoperative fluorescence. We achieved high accuracy using the features extracted by the U-Net model pre-trained for brain tumor segmentation. While the model can still be improved, it has the potential for evaluating when to administer 5-ALA to gliomas lacking typical high-grade radiographic features.

Background: Thyroid Transcription Factor-1 (TTF-1) expression in lung adenocarcinoma (LUAD) has been studied for its prognostic value in early-stage and metastatic disease. Its role in brain metastasis remains unexplored. This study investigates the predictive value and association of TTF-1 status with clinicopathological variables in patients with synchronous LUAD brain metastases.

Material and methods: In this bicentric retrospective study, 245 patients with newly diagnosed, treatment-naïve brain metastasis undergoing resection were included. Patient data were retrieved from electronic records. Outcomes included overall and progression-free survival. Statistical analysis included Kaplan-Meier estimates and Cox proportional hazards regression.

Results: Mean Ki67 index in TTF-1 negative patients was 43% [95% CI 38-48%] compared to 32% [95% CI 29-35%] in TTF-1 positive (TTF-1 +) patients (p < 0.001). Tumor volume was significantly larger in TTF-1 negative (TTF-1-) patients (mean volume 24 mL [95% CI 18-31 mL]) vs. 15 mL [95% CI 12-17 mL] in TTF-1 + patients (padjust = 0.003). Perifocal edema was smaller in TTF-1- patients (mean volume: 58 mL [95% CI 45-70 mL]) vs. 84 mL [95% CI 73-94 mL] in TTF-1 + patients (padjust = 0.077). Tumor and edema volume did not correlate. TTF-1- patients showed worse overall, intracranial, and extracranial progression-free survival. In a multivariable Cox model, positive TTF-1 status was independently associated with improved outcomes. Negative TTF-1 status was associated with increased hazard for intracranial disease progression compared to extracranial progression.

Conclusion: In synchronous LUAD brain metastases, TTF-1 negativity reflects an aggressive phenotype with larger proliferation capacity and tumor volume. Future research should explore the underlying cellular and molecular alterations of this phenotype.

Context: Chimeric antigen receptor (CAR) T cell therapy is an exciting modality of immunotherapy that has revolutionized the treatment of hematologic malignancies. However, translating this success to malignant gliomas such as glioblastoma (GBM) and diffuse midline glioma (DMG) remains a formidable challenge due to multiple biologic, anatomic, and immunologic factors. Despite these hurdles, a number of clinical trials deployed over the last decade have increased optimism for the potential of CAR T cell therapy in glioma treatment.

Evidence synthesis: We highlight historical and ongoing clinical trials of CAR T cell therapy in glioma, with a focus on key tumor-associated antigens such as IL-13Rα2, HER2, EGFR, EGFRvIII, EphA2, GD2, and B7-H3. Early studies established proof-of-concept for antigen-specific CAR T cell targeting, yet immune evasion mechanisms such as antigen downregulation and limited CAR T cell persistence remain significant obstacles. Recent approaches, including multiantigen targeting, alternative cell sources, and innovations in delivery routes offer promising strategies to overcome these challenges.

Conclusions: The rapid evolution of investigational CAR T cell therapies portends great potential for the future of glioma treatment. Future studies will need to refine antigen targeting strategies, optimize CAR T cell persistence, and integrate combinatorial approaches to fully harness the therapeutic potential of this modality and improve the therapeutic window against brain tumors.

Purpose: Prophylactic insertion of an external ventricular drainage (EVD) prior to the resection of posterior fossa metastases (PFMs) is a common approach to address postoperative transient and permanent hydrocephalus. However, predicting surgery-related hydrocephalus in the preoperative phase continues to be a challenge. This study aims to analyze the incidence, preoperatively collectable risk factors and necessity of perioperative external ventricular drainage placement after posterior fossa metastasis surgery.

Methods: All patients undergoing surgery for PFMs at the authors' neuro-oncological center between 2015 and 2021 were identified and assessed for postoperative hydrocephalus occurrence. Tumour volume, edema volume, and 4th ventricle volume were assessed on preoperative magnetic resonance imaging scans using the IntelliSpace Portal 5.0. A multivariable logistic regression analysis was performed to identify possible predictors for postoperative hydrocephalus occurrence.

Results: Postoperative hydrocephalus occurred in 14 of the 130 identified PFM patients (11%). Multivariable analysis and receiver operating characteristic (ROC) analysis revealed a 4th -ventricle-to-tumor-volume ratio ≤ 0.02 (OR 33.1, 95% CI 3.8-284.3, p = 0.001), an edema-to- tumor-volume ratio ≤ 0.85 (OR 10.6, 95% CI 2.4-47.4, p = 0.002), an imaging-morphological contact to the 4th ventricle (OR 5, 95% CI 1.4-18, p = 0.013), and multiple intracranial metastases (OR 2.4, 95% CI 1-5.9, p = 0.045) as independent predictors for surgery-related postoperative hydrocephalus occurrence.

Conclusion: The present study identifies preoperatively detectable risk factors for the occurrence of postoperative hydrocephalus following surgery for PFMs. These findings may provide guidance in clinical decision-making regarding prophylactic EVD placement.

Purpose: To investigate the molecular mechanisms underlying resistance to dopamine agonists (DA).

Methods: LC-MS/MS analysis was performed on rat pituitary neuroendocrine tumors (PitNET) cell line GH3 to identify differentially expressed proteins induced by cabergoline (CAB) treatment. A total of 180 human PITNET samples were subjected to transcriptome analysis. Immunohistochemistry (IHC) was conducted on 29 tumor samples to validate NDFIP1 alteration. A xenograft mouse model was established by subcutaneously injecting GH3 cells, with or without NDFIP1 overexpression, into nude mice to investigate tumor growth. PitNET cell lines were treated with CAB. Cell proliferation was assessed using the CCK-8, and protein expression levels were examined through Western blot analysis.

Results: CAB treatment upregulated FDFT1 and NDFIP1 protein expression in GH3 cells, with NDFIP1 showing a significant positive correlation with tumor size, as confirmed by IHC results. MMQ and GH3 cells overexpressing NDFIP1 exhibited enhanced viability and reduced sensitivity to CAB. In vivo experiments demonstrated that subcutaneous injection of NDFIP1-overexpressing GH3 cells led to enhanced tumor growth compared to parental GH3 cells. Although the total levels of PTEN remained unaltered, NDFIP1 overexpression induced PTEN nuclear translocation, potentially activating the mTOR pathway. This was supported by increased phosphorylation of key mTOR pathway components, including p-AKT and p-4EBP1, in cells overexpressing NDFIP1.

Conclusion: CAB treatment induces the upregulation of NDFIP1 in PitNET cells, which correlates with tumor size and contributes to reduced CAB sensitivity, potentially through activation of the mTOR pathway. NDFIP1 as a potential therapeutic target for overcoming DA resistance in PitNET patients.

Purpose: The incorporation of molecular markers into neuro-oncology has transformed our understanding of adult diffuse gliomas. While surgical resection is the mainstay of treatment for many patients with gliomas, surgical management strategies warrant re-exploration in the context of characteristic molecular profiles.

Methods: We reviewed the neurosurgical and neuro-oncological literature for studies investigating surgery in molecularly defined cohorts of adult diffuse gliomas.

Results: We discuss key molecular markers associated with the three subtypes of adult diffuse glioma: glioblastoma IDH-wildtype, astrocytoma IDH-mutant, and oligodendroglioma IDH-mutant and 1p/19q codeleted. We additionally discuss surgical strategies and extent of resection in these tumors, framing them in the context of key molecular alterations. Finally, we briefly discuss the practical utility of molecular markers in guiding surgical decision making.

Conclusion: Molecular markers in gliomas are of growing relevance to surgical intervention. Advancements in preoperative and intraoperative molecular diagnostics will increase the utility of molecular biomarkers in informing surgical decision-making for patients with gliomas.

Glioblastoma (GBM) is a highly aggressive primary brain tumor that carries a grim prognosis. Because of the dearth of treatment options available for treatment of GBM, Chimeric Antigen Receptor (CAR)-engineered T cell and Natural Killer (NK) therapy could provide alternative strategies to address the challenges in GBM treatment. In these approaches, CAR T and NK cells are engineered for cancer-specific immunotherapy by recognizing surface antigens independently of major histocompatibility complex (MHC) molecules. However, the efficacy of CAR T cells is hindered by GBM's downregulation of its targeted antigens. CAR NK cells face similar challenges, but, in contrast, they offer advantages as off-the-shelf allogeneic products, devoid of graft-versus-host disease (GVHD) risk as well as anti-cancer activity beyond CAR specificity, potentially reducing the risk of relapse or resistance. Despite CAR T cell therapies being extensively studied in clinical settings, the use of CAR-modified NK cells in GBM treatment remains largely in the preclinical stage. This review aims to discuss recent advancements in NK cell and CAR T cell therapies for GBM, including methods for introducing CARs into both NK cells and T cells, addressing manufacturing challenges, and providing evidence supporting the efficacy of these approaches from preclinical and early-phase clinical studies. The comprehensive evaluation of CAR-engineered NK cells and CAR T cells seeks to identify the optimal therapeutic approach for GBM, contributing to the development of effective immunotherapies for this devastating disease.