Neuro-oncology advances最新文献

Background: Imaging-based glioma monitoring is confounded by treatment-related changes. D-2-hydroxyglutarate (D-2-HG), produced by the isocitrate dehydrogenase (IDH) mutation, is detectable in cerebrospinal fluid (CSF), which can be sampled from cranial or lumbar compartments. We evaluated CSF D-2-HG as a serially accessible biomarker for IDH-mutant gliomas, including the optimal compartment for longitudinal sampling.

Methods: Lumbar and cranial CSF samples were collected from patients with IDH-mutant gliomas or IDH-wild-type central nervous system pathologies via surgical field collection, lumbar punctures, and CSF access devices. CSF D-2-HG was quantified via our CLIA-certified gas chromatography mass spectrometry assay.

Results: D-2-HG was significantly higher in cranial than lumbar CSF from IDH-mutant glioma patients. Consistent with low D-2-HG abundance in lumbar CSF, lumbar samples could not discriminate IDH-mutant gliomas from IDH-wild-type lesions. In contrast, cranial CSF D-2-HG was significantly higher in IDH-mutant gliomas than wild-type lesions, providing an adequate baseline for initial evaluations of monitoring capabilities. Across 75 samples from 7 consecutive patients with grade 4 IDH-mutant astrocytomas, serial cranial CSF D-2-HG decreased with cytoreduction, remained unchanged with stable disease, and increased with disease progression, but not pseudoprogression.

Conclusions: Serial cranial CSF D-2-HG shows promise as a monitoring biomarker for IDH-mutant gliomas.

Brain metastasis remains a significant cause of morbidity and mortality for cancer patients with limited treatment options. Single-cell RNA-seq has greatly expanded our ability to study cancer and metastasis, particularly in our assessment of tumor heterogeneity and the tumor microenvironment. In recent years, there have been several single-cell studies that have applied this technology to brain metastasis. These studies have described transcriptional characteristics of brain metastatic tumor cells and characterized immune cell changes as well as contributions of vascular and stromal cells to the brain metastatic microenvironment. This review article summarizes these studies, how they contribute to our knowledge of the molecular and cellular steps that occur in brain metastasis and in response to therapy, and how they suggest promise for future treatments.

Radiation-induced gliomas (RIGs) are rare and aggressive secondary brain tumors arising years after cranial irradiation. Their management remains challenging due to prior radiation exposure, which limits additional radiation, and a lack of effective chemotherapies. Recent studies have revealed distinct molecular profiles in RIGs with unclear clinical implications. This study presents the case of an individual who developed a high-grade glioma three decades after curative craniospinal radiation for medulloblastoma. He was treated with repeat radiation and temozolomide chemotherapy but developed recurrence with disseminated leptomeningeal disease thereafter. Molecular profiling of the tumor revealed a loss-of-function NF1 mutation and a gain-of-function PTPN11 mutation, two convergent alterations in the MAPK pathway. Based on these findings, the patient was treated with a MEK inhibitor, trametinib, and achieved durable disease control for 20 months until progression. This case underscores the importance of genomic profiling in RIGs and potential utility of molecularly targeted approaches in this population.

Meningiomas are the most common primary intracranial tumor in adults. Traditional bulk genomic and histopathological analyses have provided valuable insights into meningioma biology. Recent advances in single-cell sequencing technologies have enabled the comprehensive study of a tumor's transcriptome and epigenome at a single-cell resolution, along with spatially resolved data and functional genomics approaches. These strategies allow for the profiling of complex intratumoral and intertumoral heterogeneity, the identification of gene regulatory networks, and the characterization of distinct cell populations within the tumor microenvironment that drive tumor behavior. In this review, we examine the current landscape of single-cell omics in meningioma research and highlight opportunities for future discovery.

Vestibular schwannomas (VS) are tumors arising from Schwann cells of the vestibulocochlear nerve, often leading to hearing loss, gait imbalance, and other neurological complications. Recently, molecular profiling of VS using bulk and single-cell transcriptional and epigenetic approaches has reshaped our understanding of VS pathogenesis and challenged the long-standing view of VS being molecularly homogeneous. These integrative, multi-omic approaches reveal significant differences within VS and highlight diverse Schwann cell subpopulations and their interactions with the tumor microenvironment. Interestingly, these analyses also uncover 2 molecularly distinct groups of VS, one containing Schwann cells with an "Injury-like" phenotype that drives VS progression through immune cell recruitment and another containing more quiescent Schwann cells with decreased immune cell infiltrate. In this review, we combine insights from modern molecular analyses of VS to provide an updated view of VS pathogenesis and mechanisms of tumor growth, which may be used to inform the development of novel treatments for VS.

Single-cell and single-nuclei RNA-seq (sc/snRNA-seq) have become a central approach in cancer research, and their widespread impact has been enabled by various computational tools developed specifically for sc/snRNA-seq analysis. Nevertheless, proper analysis and interpretation of sc/snRNA-seq data requires significant expertise, and the inadequate utility of certain computational methods may lead to dubious results. To mitigate these issues, it is important to recognize the limitations of sc/snRNA-seq data, the assumptions of common methods, and to perform robust analysis. Here, I describe common pitfalls in cancer sc/snRNA-seq analysis and discuss ways to overcome them. Among others, this includes a discussion of potential errors in statistical analysis, in inference of chromosomal aberrations, in trajectory analysis, and in signature-based analysis of bulk RNA-seq data. This review may help readers to avoid common pitfalls and to perform informative analysis and careful interpretation of sc/snRNA-seq datasets in cancer.

Infiltrating gliomas are the most common primary malignant brain tumor and remain universally fatal. Over the past decade, advances in single-cell technologies, including single-cell RNA sequencing, have significantly advanced our understanding of malignant cells in glioma. These efforts have revealed extensive transcriptional heterogeneity and plasticity within glioma cells, identifying distinct cellular states and developmental programs that are discussed elsewhere. Recognizing that the tumor microenvironment constitutes sometimes more than half of the cells in gliomas, and that it has a profound impact on glioma cellular states, recent research has focused on non-malignant cells and their interactions with cancer cells. The present review reflects on lessons learned from single-cell genomics on the tumor immune microenvironment (TIME) of gliomas, as the dominant component of the tumor outside of the malignant cells and explores implications for developing effective immunotherapies.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas arising from Schwann cells and characterized by marked cellular and molecular heterogeneity. Although bulk multi-omic studies have provided valuable insights into MPNST biology, recent advances in single-cell profiling have deepened our understanding of the tumor microenvironment and molecular mechanisms underlying malignant transformation. Single cell analyses have revealed distinct Schwann cell-like, malignant neural crest-like, immune, and stromal cellular subpopulations within MPNSTs and their precursor lesions. Comparative profiling of MPNSTs, neurofibromas, and atypical neurofibromatous neoplasms of uncertain biologic potential, suggest that MPNST progression involves Schwann cell dedifferentiation into a more primitive, stem-like state. In this review, we summarize key discoveries from single-cell characterization studies, and discuss how these findings illuminate MPNST tumorigenesis, cellular plasticity, and potential therapeutic vulnerabilities.

Introduction: Older patients may be at particular risk of decline in neurocognitive function (NCF) following brain tumor resection, particularly when tumors are near-eloquent regions.

Methods: We identified 95 patients of advanced age (≥60 years) with newly diagnosed, left hemisphere, high-grade eloquent glioma who underwent a first-time awake craniotomy for tumor resection. All patients had comprehensive neuropsychological evaluations preoperatively and a subset of patients (N = 45) completed postoperative assessment.

Results: Median age at surgery was 66 years (range, 60-81) and tumors were most commonly located in the temporal (56%) and frontal (27%) lobes. Preoperatively, most patients exhibited NCF impairment on at least 1 neuropsychological test, most frequently in verbal learning (66%) and memory (71%). Localization in temporal regions conveyed greater impairment to memory, and patients with frontal tumors exhibited poorer executive functioning. Following awake resection, neurocognitive decline was most frequent in verbal learning (41%) and memory (38%). Postoperative change in neurocognitive performance was not associated with more advanced age, comorbidities, frailty, or tumor volume or extent of resection.

Conclusions: Advanced age, frailty, and medical comorbidities were not significantly associated with poorer NCF outcome. Postoperative decline was greatest when patients present with high levels of baseline functioning and tumors involve the mesial temporal lobe. Importantly, rates of baseline impairment and postoperative decline in this older age sample were similar to other cohorts, including younger patients and lower grade tumors. Findings support the relative safety of awake craniotomy for resection of eloquent glioma in advanced age individuals.