Neuro-oncology advances最新文献

Patients with rhabdoid tumor predisposition syndrome (RTPS) harbor germline alterations in the epigenetic regulator genes SMARCB1 or SMARCA4. Patients usually present with atypical teratoid/rhabdoid tumor (AT/RT) of the brain or malignant rhabdoid tumor (MRT) arising outside the central nervous system. Intensive treatment can lead to remissions, however tumors frequently recur or synchronous or metachronous tumors appear. A maintenance or secondary prevention regimen may prevent these aggressive tumors. Potential maintenance regimens may include low-dose traditional chemotherapy or different epigenetic therapies designed to target the epigenetic imbalance that drives RTs. We here review several potential maintenance regimens that may be useful in RTPS.

Background: GammaTile (GT), a form of brachytherapy utilizing cesium-131 seeds in a bioresorbable collagen tile, has gained popularity for the treatment of recurrent intracranial tumors and more recently for newly diagnosed metastases. This study reports early experience utilizing GT in upfront brain metastases with a focus on clinical applications and perioperative safety.

Methods: The STaRT Registry (NCT04427384) was queried for all patients receiving GT for upfront metastases from August 2021 to August 2023. Data regarding patient demographics, procedure details, and adverse events (AEs) were extracted and analyzed.

Results: Twenty-eight patients, median age 65 years (range 28-81), with 30 treated metastases were reported from 6 institutions. Patients had 2.8 metastases on average (range 1-15) at the time of surgery; however, most patients had a single metastasis (60.7%). The mean diameter of treated metastases was 3.4 cm (range 1.5-4.7). A median of 4.0 tiles (range 1-10) were used per tumor. The median follow-up was 3.0 months (range 1.0-11.2) with 6 attributed AEs (21.4%), including 1 grade ≥ 3 (infection). In the immediate postoperative period (<14 days), 2 patients reported pain or headache, and 1 reported facial edema. One patient developed seizures on postoperative day 8 requiring medication. At 1-month follow-up, there was 1 superficial wound infection, in a previously colonized patient, requiring surgical intervention without explantation of tiles. At 3-month follow-up, 1 patient reported facial pain not requiring treatment. There were no symptomatic hematomas.

Conclusions: GT demonstrates a favorable safety profile in upfront brain metastases with a 3.6% rate of serious AEs (grade ≥ 3) within 90 days of the procedure.

Spinal meningiomas comprise 25%-46% of all primary spinal tumors. While the majority are benign and slow-growing, when left untreated, they can result in significant neurological decline. Emerging clinical, imaging, and molecular data have begun to reveal spinal meningiomas as distinct tumor subtypes compared to their intracranial counterparts. Moreover, recent studies indicate molecular and genetic subtype heterogeneity of spinal meningiomas both within and across the classically defined WHO grades. In the current review, we focus on recent advances highlighting the epidemiological, pathological, molecular/genetic, and clinical characteristics of spinal meningiomas. Furthermore, we explore patient and tumor-specific factors that predict prognosis and postoperative outcomes. We highlight areas that require further investigation, specifically efforts aimed at linking unique molecular, genetic, and imaging characteristics to distinct clinical presentations to better predict and manage patient outcomes.

Background: Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood central nervous system tumor. Diagnosis and monitoring of tumor response to therapy is based on magnetic resonance imaging (MRI). MRI-based analyses of tumor volume and appearance may aid in the prediction of patient overall survival (OS).

Methods: Contrast-enhanced T1- and FLAIR/T2-weighted MR images were retrospectively collected from children with classical DIPG diagnosed by imaging (n = 43 patients). MRI features were evaluated at diagnosis (n = 43 patients) and post-radiation (n = 40 patients) to determine OS outcome predictors. Features included 3D tumor volume (T_wv), contrast-enhancing tumor core volume (T_c), T_c relative to T_wv (T_C/T_wv), and T_wv relative to whole brain volume. Support vector machine (SVM) learning was used to identify feature combinations that predicted OS outcome (defined as OS shorter or longer than 12 months from diagnosis).

Results: Features associated with poor OS outcome included the presence of contrast-enhancing tumor at diagnosis, >15% T_c/T_wv post-radiation therapy (RT), and >20% ∆Tc/T_wv post-RT. Consistently, SVM learning identified T_c/T_wv at diagnosis (prediction accuracy of 74%) and ∆T_c/T_wv at <2 months post-RT (accuracy = 75%) as primary features of poor survival.

Conclusions: This study demonstrates that tumor imaging features at diagnosis and within 4 months of RT can predict differential OS outcomes in DIPG. These findings provide a framework for incorporating tumor volume-based predictive analyses into the clinical setting, with the potential for treatment customization based on tumor risk characteristics and future applications of machine-learning-based analysis.

Background: Patients with brain tumors demonstrate heterogeneous patterns of cognitive impairment, likely related to multifactorial etiologies and variable tumor-specific factors. Cognitive phenotyping offers a patient-centered approach to parsing heterogeneity by classifying individuals based on patterns of impairment. The aim of this study was to investigate the neuroanatomical patterns associated with each phenotype to gain a better understanding of the mechanisms underlying impairments.

Methods: Patients with primary brain tumors were recruited for a prospective, observational study. Patients were cognitively phenotyped using latent profile analysis in a prior study, revealing 3 distinct groups: generalized, isolated verbal memory, and minimal impairment. Whole brain cortical thickness (CT), fractional anisotropy, and mean diffusivity (MD) were compared across phenotypes, and associations between imaging metrics and cognitive scores were explored.

Results: Neurocognitive, structural MRI, and diffusion MRI data were available for 82 participants at baseline. Compared to the minimal impairment group, the generalized impairment group showed a widespread, bi-hemispheric pattern of decreased CT (P-value range: .004-.049), while the verbal memory impairment group showed decreased CT (P-value range: .006-.049) and increased MD (P-value range: .015-.045) bilaterally in the temporal lobes. In the verbal memory impairment group only, increased parahippocampal MD was associated with lower verbal memory scores (P-values < .01).

Conclusions: Cognitive phenotypes in patients with brain tumors showed unique patterns of brain pathology, suggesting different underlying mechanisms of their impairment profiles. These distinct patterns highlight the biological relevance of our phenotyping approach and help to identify areas of structural and microstructural vulnerability that could inform treatment decisions.

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.