Neuro-oncology advances最新文献

Background: Glioblastoma (GBM) lacks effective therapies for recurrent disease. Unlike cancers with successful fusion-targeted treatments (eg BCR-ABL1 in CML), the incidence and therapeutic potential of gene fusions in GBM remain unclear. We analyzed a large genomic database to define fusion frequency and molecular associations.

Methods: 4800 IDH-wildtype GBM samples (WHO 2021) underwent NextGen DNA sequencing (592-gene panel/whole exome) and Whole Transcriptome Sequencing for fusions at Caris Life Sciences. Fisher-Exact/Chi-Square tests, adjusted by Benjamini-Hochberg (q < 0.05), assessed significance.

Results: Pathogenic fusions occurred in 428 (8.9%) samples, primarily FGFR3 (37%, n = 159; FGFR3: TACC3, n = 134), MET (21%, n = 92), and EGFR (20%, n = 87). Pathogenic or likely pathogenic fusions included NTRK2 (n = 27), PDGFRA (n = 23), ROS1 (n = 14), and BRAF (n = 10). Fusion-positive tumors had higher MET (7.5% vs. 0.7%), FGFR3 (5% vs. 0.2%), CDK4 (17% vs. 11%), and MDM2 (12% vs. 7.5%) amplifications, but lower EGFR mutations (6.1% vs. 18%), amplifications (6.1% vs. 18%), and EGFRvIII (11.9% vs. 22.5%) (all q < 0.05). Median survival was 16.6 months (fusion-positive) vs. 15.5 months (fusion-negative) (P = 0.043). Tyrosine kinase inhibitor (TKI)-treated fusion-positive patients (n = 37) showed no significant survival benefit (18.4 vs. 16.5 months, P = .971).

Conclusions: Approximately 9% of GBMs harbor targetable fusions, with five genes (FGFR3, MET, EGFR, NTRK2, PDGFRA) comprising 8%. These findings support multi-arm clinical trials to evaluate targeted therapies, potentially improving outcomes for molecularly defined GBM subgroups.

Abstract: BackgroundSeizures are a common and disabling symptom of adult-type diffuse gliomas, affecting quality of life and potentially influencing tumor progression. Despite their clinical significance, seizure outcomes are often underreported or heterogeneously measured in clinical trials.

Objective: To assess how seizure outcomes are reported in clinical trials for adult-type diffuse glioma.

Methods: We systematically reviewed glioma clinical trials initiated after January 1, 2010, through June 16, 2025, on ClinicalTrials.gov that included seizure-related outcomes. Each trial was manually screened to characterize how seizures were defined, measured, and categorized.

Results: Of 2,801 clinical trials identified, 65 (2.3%) included seizure-related outcomes. Among these, 20 designated seizures as a primary outcome, though many grouped them within broader safety endpoints. Seizures were often listed as secondary outcomes (n = 23), adverse events (n = 11), or within quality-of-life assessments (n = 8). Reporting was highly variable; many trials used binary metrics. As few as 9 trials systematically assessed seizures using International League Against Epilepsy (ILAE) guidelines for seizure tracking (eg seizure diaries or structured EEG evaluation), and only 7 reported outcomes with standardized scales such as the ILAE outcome classification or the Engel classification, with rare use of newer tools such as the Seizure Control Composite Index.

Conclusions: Despite their clinical significance, seizure outcomes are rarely and heterogeneously reported in clinical trials for adult-type diffuse gliomas. Incorporating standardized, seizure-specific endpoints may better align glioma research with patient-centered and disease-specific outcomes.

Background: Desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA) is a rare, low-grade tumor of infants. They are usually composed of a mixed astrocytic and neuronal component with desmoplastic stroma and embryonal-looking areas. Despite some recent reports, clinical, morphological and molecular features of DIG/DIAs are still not well characterized. Here, we present a series of 8 DIG/DIA cases.

Methods: Hacettepe University and Koc University Hospital, Departments of Pathology, databases were screened for DIG/DIA. Eight patients were identified. All the slides were reevaluated, and patients' clinical data were obtained. All cases were tested for BRAF V600 mutation and 3 BRAF V600 wild-type cases were sequenced.

Results: Median age at the diagnosis was 5.5 months (4-30 months). The female to male ratio was 6:2. Two cases recurred. Four cases showed BRAF p. V600 mutation. Of those BRAF p. V600 wild-type cases, one harbored TMEM106B::BRAF fusion, described for the first time in a DIG/DIA case.

Conclusions: DIG/DIA is a low-grade tumor seen in early childhood and characterized by an indolent clinical course. The most common molecular signature of these tumors is BRAF alterations, including rearrangements. The primary differential diagnosis is infant-type hemispheric glioma and given the similarities, pathologists must remain careful to ensure accurate diagnosis.

Background: With less than 650 published cases, combination tumors of the nervous system, that is, two locally intertwined but histologically distinct tumor entities, pose a rare constellation, its clinical relevance still being a matter of debate.

Methods: A consecutive cohort of 2530 patients operated on meningioma or hemangioblastoma between 2009 and 2021 was retrospectively screened for concomitant neoplastic disease to identify cases of combination tumors. Additionally, all available literature published between 1930 and 2021 was compiled in a comprehensive review.

Results: Our cohort comprised 144 cases of patients with concomitant neoplastic disease and among those 10 instances of combination tumors. Another instance occurred after our screening period. Benign entities were meningiomas, but no hemangioblastoma. Contributing tumors were adenocarcinomas, lymphoma, glioblastoma, pituitary neuroendocrine tumors, and neurinoma. Patients' age ranged from 41 to 81 years with a slight preference for females. Identification of concomitant neoplasia was first achieved due to the combination tumor in about half of our cases. For the rest, median latency until manifestation of the combination tumor was 9 years. The odds ratio for a combination tumor was 17.6 for meningioma patients with known concomitant neoplasia, but it was preoperatively suspected in 18.2% of cases only.

Conclusion: Presenting one of the largest clinical series, we provide evidence that known concomitant neoplasia in patients with suspected meningioma should make clinicians consider a combination tumor. Confirmation may lead to therapeutic consequences, largely contributing to long-term prognosis. Furthermore, we present the most extensive literature review on the matter to date.

Abstract: BackgroundPrimary central nervous system lymphoma (PCNSL) is a rare and aggressive malignancy that frequently mimics other central nervous system (CNS) diseases, leading to diagnostic delays. Given its often nonspecific radiological presentation, PCNSL remains a diagnostic challenge, however early diagnosis and timely initiation of treatment are critical. This study aimed to evaluate diagnostic timelines and their influencing factors, treatment patterns, and their impact on survival in patients with PCNSL.

Methods: We retrospectively analyzed 125 patients diagnosed with PCNSL at a single tertiary care referral center between 2008 and 2021. Clinical, radiological, and histopathological data were collected to assess factors influencing diagnostic delay, treatment decisions, and patient outcomes.

Results: The median age at diagnosis was 68 years (21-89) and median Karnofsky Performance Status (KPS) was 70% (10-100). The median time from initial clinical symptom to histopathologically confirmed diagnosis was 37 days (4-749). The median time from first neuroimaging to confirmed diagnosis was 12 days (2-225). A shorter diagnostic interval (≤ 12 days) was associated with significantly improved overall survival and progression-free survival (PFS) (P < .05). In a multivariate Cox proportional hazards model, predictors of OS were KPS ≥70% (P < .003), preserved renal function (GFR > 60 mL/min, P < .027), and MTX-based chemotherapy (P < .001). Further, diagnostic delay (>12 days) emerged as an independent predictor of PFS (P < .024).

Conclusion: Our study underscores the prognostic impact of diagnostic delay in PCNSL. Renal function and KPS emerged as independent OS markers. MTX-based chemotherapy remains the standard of care, with autologous hematopoietic stem cell transplantation providing best survival outcomes in eligible patients.

Background: Large vestibular schwannomas (VSs), particularly Koos grade III-IV, often require a balance between tumor control and cranial nerve preservation. This meta-analysis evaluates outcomes of planned subtotal or near-total resection (STR/NTR) followed by stereotactic radiosurgery (SRS) and explores prognostic factors.

Methods: Following PRISMA guidelines, a systematic review was conducted across four databases for studies published from January 2017 to January 2025, reporting outcomes of STR/NTR followed by SRS in large VSs. Pooled proportions for tumor control, facial nerve preservation (House-Brackmann grade I-II), and hearing preservation (Gardner-Robertson class I-II) were calculated using random-effects models. Heterogeneity, publication bias, and risk of bias were assessed. Meta-regression evaluated the impact of preoperative cranial nerve function and tumor characteristics.

Results: Fourteen studies encompassing 934 patients were included. The pooled tumor control rate was 80%, with facial nerve function preserved in 85% and serviceable hearing in 43%. Meta-regression indicated that better preoperative HB and GR scores were significantly associated with superior outcomes (P < .05), while cystic tumor morphology correlated with reduced tumor control following SRS (P < .05). Compared to prior meta-analyses of gross-total resection (GTR), the combined STR/NTR plus SRS approach demonstrated superior nerve preservation and functional outcomes.

Conclusions: STR/NTR followed by SRS is an effective treatment for large VSs, optimizing tumor control while enhancing facial nerve and hearing preservation compared to GTR alone. Patients with favorable preoperative function benefit most. Cystic tumors may require closer follow-up due to increased recurrence risk.

Abstract: BackgroundDiaphanous-related formin 3 (DIAPH3) is a member of the formin family, a group of proteins that regulate actin and microtubule dynamics. During mitosis, DIAPH3 localizes specifically to the centrosome. Its loss destabilizes microtubules and disrupts mitotic spindle polarity, leading to multipolar mitoses and abnormal chromosome segregation, which ultimately causes aneuploidy in daughter cells.

Methods: We investigated DIAPH3 expression in glioma samples-including low-grade and high-grade gliomas-using publicly available datasets (The Cancer Genome Atlas and a single-cell RNA-seq study). We also explored the impact of DIAPH3 expression on aneuploidy in cultured glioblastoma cells.

Results: DIAPH3 expression was specifically increased in grade 4 gliomas. However, its prognostic value did not surpass that of the WHO CNS5 glioma classification. DIAPH3 was predominantly expressed in mitotic cells and showed strong coexpression with genes involved in cell division, particularly those regulating mitotic progression and chromosome segregation. Several transcription factors known to drive proliferation and cancer progression may regulate DIAPH3 expression. In glioblastoma cell lines, we confirmed that DIAPH3 is upregulated during mitosis and that its knockdown increases aneuploidy.

Conclusions: These findings confirm the role of DIAPH3 in chromosome segregation in clinical glioma samples and demonstrate its association with high-grade, poor-prognosis gliomas.

"Pseudoprogression" following immune checkpoint inhibitors (ICI) in glioblastoma is often considered in case of radiographic progression. To better characterize the frequency of this phenomenon in glioblastoma, we reviewed the imaging response characteristics of a total of 55 patients treated with ICI in the setting of recurrent (n = 45) or newly diagnosed (n = 10) disease. There was no evidence of pseudoprogression related to ICI-monotherapy in the entire cohort.

Background: Accurate classification of glioma subtypes is essential for personalized treatment, yet current diagnostic approaches rely on invasive procedures to determine molecular profiles. This study aims to enhance non-invasive glioma classification by integrating metabolic imaging with advanced unsupervised learning.

Methods: Whole-brain 3D Magnetic Resonance Spectroscopic Imaging (MRSI) was performed at 3 Tesla. From 26 scanned patients, 12 gliomas (5 astrocytomas, 5 oligodendrogliomas, 2 glioblastomas) that passed strict quality-control criteria were included for analysis. Spectral decomposition was performed using Global Non-Negative Matrix Underapproximation (G-NMU), and tumor subtype classification was achieved with Uniform Manifold Approximation and Projection (UMAP) followed by K-means clustering.

Results: The proposed framework was able to classify tumor types with an accuracy of 99.65% and an AUC of 99.07. Clear subtype-specific metabolic fingerprints were validated by hierarchical clustering and UMAP embeddings, emphasizing 2HG, serine, and inositol as important classification drivers.

Conclusions: This study demonstrates that whole-brain MRSI spectral decomposition based on G-NMU is a reliable non-invasive method for classifying gliomas. In contrast to spectral fitting on prior-knowledge basis sets, G-NMU accurately separates astrocytoma, oligodendroglioma, and glioblastoma by extracting metabolic features without making assumptions about the tumor metabolic composition. These results suggest that integration of metabolic imaging and unsupervised learning into clinical workflows may improve molecular stratification for noninvasive glioma diagnosis.

Abstract: BackgroundMost children with central nervous system (CNS) tumors reside in low- and middle-income countries (LMICs), with limited availability of trained pediatric neuro-oncologists.

Methods: Using a series of structured interviews of physicians who had served as global mentors or mentees in pediatric oncology, we identified mentorship, leadership, and clinical training as key components necessary to virtually train pediatric oncologists in LMICs to become leading pediatric neuro-oncologists while they remain in their home countries. Thus, the St Jude Global Virtual Pediatric Neuro-oncology Fellowship (VPNOF) was designed to incorporate mentorship with global and loco-regional mentors to aid in each fellow's career and institutional goal setting and clinical training involving virtual tumor boards and didactics and ad-hoc case discussions, enabling fellows to manage patients at their home institution. Fellows traveled to their mentors' institutions twice for four-week clinical rotations.

Results: In 2022 and 2023, eleven fellows were selected, representing 10 LMICs. The 2-year fellowship led to the establishment of multi-disciplinary approaches, increased patient volume, increased use of evidence-based practices, 33 abstract presentations, and publication of four journal articles.

Conclusions: The VPNOF is an innovative approach leveraging global mentorship to train pediatric oncologists in resource-limited settings to become pediatric neuro-oncologists, which has led to the successful implementation of new practice paradigms to improve the quality of care for children with CNS tumors in LMICs.