Neuro-oncology advances最新文献

Background: Lisavanbulin (BAL101553) is a small, lipophilic, oral microtubule destabilizer with promising antitumoral activity observed in preclinical glioblastoma (GBM) models.

Methods: This multicenter phase 1 study sought to determine the MTD of oral Lisavanbulin in combination with standard RT (60 Gy/30 fractions) but without temozolomide in patients with newly diagnosed MGMT promoter unmethylated GBM (uGBM). Dose escalation followed a modified 3 + 3 design. Secondary objectives included estimation of OS and PFS and pharmacokinetic analysis.

Results: Twenty-six patients with uGBM (median age, 63 years, 42.3% male, 61.5% with gross total resection, median Karnofsky performance status 80) were enrolled; 2 tumors had an IDH1 mutation. Predefined dose levels of Lisavanbulin, administered daily concomitantly with RT, were: 4 mg (5 pts), 6 mg (5 pts), 8 mg (7 pts), 12 mg (5 pts), and 15 mg (4 pts). The initial starting dose was 8 mg. Due to grade 4 aseptic meningoencephalitis in the first patient, the dose was decreased to 4 mg. Dose escalation resumed and continued to 15 mg with dose-limiting toxicities of grade 2 confusion and memory impairment observed at 12 mg. Avanbulin exposures increased in a relatively dose-proportional manner with increasing oral dose of Lisavanbulin from 4 to 15 mg.

Conclusions: Lisavanbulin in combination with RT was considered safe up to the highest predefined oral dose level of 15 mg daily.

Background: Meningiomas are the most common primary central nervous system tumors in adults. Although generally benign, a subset is of higher grade and ultimately fatal. Around half of all meningiomas harbor inactivating mutations in NF2, leading to deregulation of oncogenic YAP1 activity. While benign NF2 mutant meningiomas exhibit few genetic events in addition to NF2 inactivation, aggressive high-grade NF2 mutant meningiomas frequently harbor a highly aberrant genome. It is unclear if NF2 mutant meningiomas of different grades are equally reliant on YAP activity.

Methods: We analyzed bulk and single-cell RNA-Seq data from a large cohort of human meningiomas for the expression of YAP1 target genes and Hippo effectors as well as in vitro cell line experiments.

Results: Aggressive NF2 mutant meningiomas harbor decreased expression levels of YAP1 target genes and increased expression levels of the YAP1 antagonist VGLL4 and the upstream regulators FAT3/4 compared to their benign counterparts. Decreased expression of YAP1 target genes as well as high expression of VGLL4 and FAT3/4 is significantly associated with an increased risk of recurrence. In vitro, overexpression of VGLL4 resulted in the downregulation of YAP activity in benign NF2 mutant meningioma cells, confirming the direct link between VGLL4 expression and decreased levels of YAP activity observed in aggressive NF2 mutant meningiomas.

Conclusions: Our results shed new insight into the biology of benign and aggressive NF2 mutant meningiomas and may have important implications for the efficacy of therapies targeting oncogenic YAP1 activity in NF2 mutant meningiomas.

Background: The use of mind-body, cognitive-behavioral, and physical activity interventions have shown efficacy for improving symptom burden and functional limitations in other cancers; however, these strategies have not been widely implemented within neuro-oncology. This systematic review describes the current landscape and the impact of these interventions on adolescent and adult patients with brain tumors, which may guide the development of future interventions.

Methods: A systematic search of PubMed, Embase, and Web of Science was performed using preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines with predefined eligibility criteria. Twenty-nine studies met the inclusion criteria and were selected for review.

Results: There was promising evidence for the feasibility and efficacy of mind-body and physical activity interventions for improving mood and quality of life, as well as enhanced physical functioning following aerobic and strength-based interventions. Results were mixed for cognitive-behavioral interventions, likely due to underpowered analyses. Interventions tested in pediatric patients also showed improvements in fatigue, mood, and quality of life, though these individuals represented a small proportion of the pooled sample.

Conclusions: Findings suggest that mind-body and physical activity interventions can improve both physical and psychological health for patients with brain tumors, though additional well-designed clinical trials are needed to better establish efficacy.

Background: Variations in survival among patients with oligodendroglioma are unexplained by known prognostic factors. To assess the impact of peripheral immune profiles on prognosis, we applied immunomethylomics analyses-DNA methylation of archived whole blood samples, to characterize immune cells.

Methods: We compared the proportions of immune cells from patients with oligodendroglioma to other glioma subtypes and controls. We used recursive partitioning analysis (RPA) within the oligodendrogliomas to correlate with survival.

Results: Patients with oligodendrogliomas (141) were median age at diagnosis of 44 years; 57% male; 75% White; 60% prior chemotherapy; and 25% on dexamethasone at sample collection. Patients with oligodendrogliomas had immune profiles more similar to controls than other glioma subtypes, though with notably lower B-cells. RPA of patients with oligodendrogliomas delineated 2 survival groups based on an interaction between age and B-naïve cells. Patients with longer survival (median 24.2 years) were ≤42 years of age with higher B-naïve cells versus worse survival (median 16.9 years) who were ≤42 years of age with lower B-naïve cells or >42 years of age (P = .00032). Patients with worse survival also had lower CD4- and CD8-naïve T-cells. Similar immune profiles were observed in an independent cohort of oligodendroglioma patients prior to surgery.

Conclusions: Peripheral blood immune profiles in oligodendroglioma suggested that younger patients with lower B-naïve cells experienced shorter survival. Though our findings lack of validation cohort and use a heterogenous patient population, they suggest peripheral blood immune profiles may be prognostic for patients with glioma and warrant further investigation.

Background: Evaluating longitudinal changes in gliomas is a time-intensive process with significant interrater variability. Automated segmentation could reduce interrater variability and increase workflow efficiency for assessment of treatment response. We sought to evaluate whether neural networks would be comparable to expert assessment of pre- and posttreatment diffuse gliomas tissue subregions including resection cavities.

Methods: A retrospective cohort of 647 MRIs of patients with diffuse gliomas (average 55.1 years; 29%/36%/34% female/male/unknown; 396 pretreatment and 251 posttreatment, median 237 days post-surgery) from 7 publicly available repositories in The Cancer Imaging Archive were split into training (536) and test/generalization (111) samples. T1, T1-post-contrast, T2, and FLAIR images were used as inputs into a 3D nnU-Net to predict 3 tumor subregions and resection cavities. We evaluated the performance of networks trained on pretreatment training cases (Pre-Rx network), posttreatment training cases (Post-Rx network), and both pre- and posttreatment cases (Combined networks).

Results: Segmentation performance was as good as or better than interrater reliability with median dice scores for main tumor subregions ranging from 0.82 to 0.94 and strong correlations between manually segmented and predicted total lesion volumes (0.94 < R ² values < 0.98). The Combined network performed similarly to the Pre-Rx network on pretreatment cases and the Post-Rx network on posttreatment cases with fewer false positive resection cavities (7% vs 59%).

Conclusions: Neural networks that accurately segment pre- and posttreatment diffuse gliomas have the potential to improve response assessment in clinical trials and reduce provider burden and errors in measurement.

Background: Meningiomas are the most common primary tumor in the central nervous system. About 15%-20% are aggressive and tend to recur and progress despite conventional treatment. Bevacizumab has been found to be effective in the treatment of refractory meningiomas in retrospective studies. The Response Assessment in Neuro-Oncology (RANO) criteria are widely used to assess the effect of treatment. Recent studies suggest that the 3D volumetric growth rate (3DVGR) may be more accurate for irregularly shaped tumors. The aim of this study was to compare these approaches.

Methods: Twenty patients with refractory meningiomas were treated with bevacizumab. Tumors were measured using the RANO criteria and 3DVGR before and after initiation of treatment by 2 radiologists using PACS and BRAIN LAB iPLAN software, respectively, findings were compared.

Results: A total of 46 lesions were included in the final analysis. Bevacizumab was shown to be effective by both assessment methods. According to RANO criteria, the rate of progression-free survival at 6 months was 47%. According to 3DVGR, all lesions were characterized by either a decrease in volume or stable growth after treatment initiation. A decrease in 3DVGR of 50% or more was found in 90% of lesions. In several patients, there were discordances between RANO criteria and 3DVGR.

Conclusions: Although RANO criteria are widely accepted for evaluation of response to treatment of meningiomas, 3DVGR seems to generate more precise measurements of irregularly shaped tumors. The results of this study offer important evidence that bevacizumab may be beneficial in treating refractory meningiomas.

Background: FOXR2-activated central nervous system (CNS) neuroblastoma (CNS NB-FOXR2) is a recently identified subtype of brain tumor characterized by the elevated expression of the transcription factor FOXR2 mainly due to genomic rearrangements. However, the precise pathogenic mechanisms, including the cell type of origin, remain elusive.

Methods: A gene expression analysis of patient tumors was performed to identify putative cell types of origin. Based on this prediction, a new human embryonic stem cell-based model was developed to validate the origin and to examine the molecular and cellular mechanisms underlying the formation of CNS NB-FOXR2.

Results: Our data showed that CNS NB-FOXR2 tumors express a high level of lineage marker genes associated with the medial ganglionic eminence (MGE), a transient structure located in the developing ventral forebrain. Our model confirmed the cell-type-specific effect of FOXR2 on the proliferation and in vivo tumorigenicity. Additionally, we found that FOXR2 overexpression activated the MEK/ERK signaling pathway through a suppression of the endogenous RAS inhibitor DIRAS3. The MEK inhibitor trametinib suppressed the proliferation of FOXR2-expressing MGE progenitors more than nonexpressing cells.

Conclusions: Our study collectively demonstrates that MGE progenitors are the cell of origin of CNS NB-FOXR2 and that FOXR2 activates the MEK/ERK signaling pathway, providing a potential therapeutic target.

Primary central nervous system (CNS) tumors affect tens of thousands of patients each year, and there is a significant need for new treatments. Macrophage migration inhibitory factor (MIF) is a cytokine implicated in multiple tumorigenic processes such as cell proliferation, vascularization, and immune evasion and is therefore a promising therapeutic target in primary CNS tumors. There are several MIF-directed treatments available, including small-molecule inhibitors, peptide drugs, and monoclonal antibodies. However, only a small number of these drugs have been tested in preclinical models of primary CNS tumors, and even fewer have been studied in patients. Moreover, the brain has unique therapeutic requirements that further make effective targeting challenging. In this review, we summarize the latest functions of MIF in primary CNS tumor initiation and progression. We also discuss advances in MIF therapeutic development and ongoing preclinical studies and clinical trials. Finally, we discuss potential future MIF therapies and the strategies required for successful clinical translation.

The emergence of advanced systemic therapies added to the use of cranial radiation techniques has significantly improved outcomes for cancer patients with multiple brain metastases (BM), leading to a considerable increase in long-term survivors. In this context, the rise of radiation-induced cognitive toxicity (RICT) has become increasingly relevant. In this critical narrative review, we address the controversies arising from clinical trials aimed at mitigating RICT. We thoroughly examine interventions such as memantine, hippocampal avoidance irradiation during BM treatment or in a prophylactic setting, and the assessment of cognitive safety in stereotactic radiosurgery (SRS). Our focus extends to recent neuroscience research findings, emphasizing the importance of preserving not only the hippocampal cortex but also other cortical regions involved in neural dynamic networks and their intricate role in encoding new memories. Despite treatment advancements, effectively managing patients with multiple BM and determining the optimal timing and integration of radiation and systemic treatments remain areas requiring further elucidation. Future trials are required to delineate optimal indications and ensure SRS safety. Additionally, the impact of new systemic therapies and the potential effects of delaying irradiation on cognitive functioning also need to be addressed. Inclusive trial designs, encompassing patients with multiple BM and accounting for diverse treatment scenarios, are essential for advancing effective strategies in managing RICT and the treatment of BM patients.

Background: Radiotherapy (RT) plays an integral role in the management of low-grade gliomas (LGG). Late toxicity from RT can cause progressive neurocognitive dysfunction. Radiation-induced damage to the hippocampus (HCP) plays a considerable role in memory decline. Advancements in photon planning software have resulted in the development of multi-criteria optimization (MCO) and HyperArc technologies which may improve HCP sparing while maintaining planning target volume (PTV) target coverage.

Methods: Three planning methods for hippocampal sparing (HS) were compared, volumetric modulated arc therapy (VMAT) without HS (VMAT_noHS), VMAT with HS (VMAT_HS), MCO with HS (MCO_HS), and HyperArc with HS (HyperArc_HS).

Results: Twenty-five patients were identified. The contralateral HCP was spared in 16 patients and bilateral HCP in 9 patients with superiorly located tumors. All 3 HS planning techniques showed significant reductions in dose to the spared HCP in contralateral cases but only VMAT_HS and MCO_HS achieved this in bilateral cases (P < .008). Only MCO_HS was superior to VMAT_HS in lowering the dose to both contralateral HCP and bilateral HCP in all measured metrics (P < .008). PTV and OAR (organ at risk) dose constraints were achieved for all plans.

Conclusions: This retrospective dosimetric study demonstrated the feasibility of HS for low-grade glioma. All 3 HS planning techniques achieved significant dose reductions to the spared contralateral hippocampus, but only MCO_HS and VMAT_HS achieved this in bilateral cases. MCO was superior to other planning techniques for sparing both bilateral and contralateral hippocampi.