Neuro-oncology advances最新文献

Background: Isocitrate dehydrogenase (IDH)-mutant gliomas generally have a better prognosis than IDH-wild-type glioblastomas, and the extent of resection significantly impacts prognosis. However, there is a lack of integrated tools for predicting outcomes based on molecular subtypes and treatment modalities. This study aimed to identify factors influencing gross total resection (GTR) rates and to develop a clinical prognostic tool for IDH-mutant gliomas.

Methods: We analyzed 650 patients with IDH-mutant gliomas from 3 Chinese medical centers (Shanghai, Hong Kong, and Zhengzhou). Data included age, sex, extent of resection, radiotherapy status, tumor grade, histology, and molecular markers (1p19q, TERT promoter, BRAF, EGFR, 10q). Patients were categorized based on GTR status, and a nomogram predicting 3-, 5-, and 10-year overall survival (OS) was developed using Cox proportional hazards regression and validated with time-dependent ROC and calibration plot analyses.

Results: Non-GTR was associated with diffuse astrocytoma (73.0% vs. 53.5%), 1p19q non-codeletion (67.9% vs. 48.7%), and wildtype TERT promoter (63.6% vs. 52.4%). The nomogram, incorporating age, TERT promoter status, extent of resection, grade, and radiotherapy status, demonstrated strong discriminatory ability (AUC > 0.75) and good calibration. Decision curve analysis indicated that it outperformed WHO grade-based classification in identifying high-risk patients. An online calculator was developed for clinical use (http://www.szflab.site/nomogram/).

Conclusion: We developed and validated a nomogram and online tool that integrates molecular and clinical factors for predicting outcomes in IDH-mutant gliomas, enhancing clinical decision-making.

Background: Few studies have evaluated predictive factors of isolated pituitary stalk thickening (iPST) in children.

Methods: In this retrospective study, radiology, endocrinology, and neuro-oncology databases were interrogated to identify patients with iPST between January 2000 and June 2019. A blinded, longitudinal assessment of MRIs was performed using quantitative, semi-quantitative, and qualitative metrics. Neuroimaging parameters were correlated to clinical parameters.

Results: Forty-seven patients were identified, with 40 meeting the inclusion criteria. Median age at baseline MRI was 9.6 years (range 0.9-17.5) with median follow-up of 5.2 years (range 0.3-18.6). Twenty-five (63%) were female. Thirty-four (85%) had pituitary dysfunction, including 31 with central diabetes insipidus (cDI). cDI was not predictive of proliferative disease (PfD): 69% of those with presumed primary hypophysitis (PPH) versus 93% with PfD (P = .1). Fourteen (35%) patients were diagnosed with PfD (germinoma = 8, Langerhans cell histiocytosis = 5, lymphoma = 1) at median of 1.3 years (range 0.3-4.0) after initial MRI. Progressive thickening of the stalk over time was associated with PfD (86% vs 4% in PPH, P < .0001), as was thickening of the entire stalk (56% in PfD vs 27% in PPH, P < .0001) with different imaging trends over time observed in PfD versus PPH. A "sack of marbles" appearance with heterogeneous enhancement on post-contrast imaging was associated with germinoma.

Conclusions: In this cohort, 35% of children with iPST were diagnosed with PfD. The association of cDI and PfD was not statistically significant. Progressive thickening of the entire stalk was predictive of PfD and a "sack of marbles" pattern was found to be highly suggestive of germinoma.

Background: Postoperative pediatric cerebellar mutism syndrome (ppCMS) poses serious morbidity after posterior fossa tumor surgery. Neuroimaging studies aim to understand its pathophysiology, yet these vary in methodology and outcome measures. Therefore, we systematically reviewed the current literature to evaluate the evidence for differences in neuroimaging features between children with and without ppCMS.

Methods: Following PRISMA guidelines, a systematic review was conducted by searching for original articles on neuroimaging in children undergoing posterior fossa tumor surgery, comparing patients with and without ppCMS. Articles were selected based on predefined eligibility criteria. Data were systematically extracted, and risk of bias was evaluated.

Results: From the 866 articles identified, 50 studies fulfilled the inclusion criteria. Studies were categorized into 3 imaging domains: structural, diffusion, and functional imaging. Risk of bias assessment revealed a medium risk in most articles, predominantly due to unclear ppCMS definition and qualitative image analysis without blinding for ppCMS diagnosis. Preoperative structural imaging showed the association of ppCMS with midline tumor localization and involvement of the brainstem, superior cerebellar peduncle (SCP), or middle cerebellar peduncle. Postoperative structural and diffusion imaging highlighted SCP injury with reduced white matter integrity, while functional imaging demonstrated hypoperfusion in frontal lobes. Late follow-up showed T2-weighted hyperintensities in the inferior olivary nuclei of ppCMS patients.

Conclusion: Neuroimaging features suggest that ppCMS is associated with efferent cerebellar pathway injury and hypoperfusion in frontal lobes, with level 2 a/b evidence. Large-scale prospective longitudinal neuroimaging studies comparing pre- and postoperative imaging are needed to further elucidate the pathophysiological mechanism of ppCMS.

Background: This study is a phase II clinical trial to evaluate the efficacy, safety, and tolerability of the blood-brain barrier (BBB) permeable peptide-paclitaxel conjugate ANG1005 in patients with recurrent high-grade glioma (HGG) (NCT01967810).

Methods: Seventy-three patients were enrolled in 3 separate arms-recurrent glioblastoma (GBM) (Arm 1), bevacizumab refractory GBM (Arm 2), and grade 3 anaplastic gliomas (AGs) (Arm 3). The study was started in October 2013, and the data were locked on September 29, 2017. Safety was evaluated for all three arms (n = 73), and the primary endpoint for Arms 1 and 3 was objective response rate (ORR), and Arm 2 primary endpoint was progression-free survival rate at 3 months (PFS3).

Results: Overall, the safety of ANG1005 was found to be consistent with a taxane toxicity profile. Otherwise, the primary efficacy endpoints of ORR and PFS were not met. The most common adverse events (AEs) were hematologic (32.9%), alopecia (31.5%), and fatigue (30.1%). The median PFS was 1.4 months (95% CI: 1.4, 2.1) and similar across all the treatment arms. The median overall survival was 13.4 months (95% CI: 3.4, 14.6) in Arm 1, 5.8 months (95% CI: 1.9, 9.7) in Arm 2, and 18.2 months (95% CI: 10.7, 35.3) in Arm 3.

Conclusion: A dose of 600 mg/m² was determined to be safe in this study. However, the primary efficacy endpoint was not met in the NCT01967810-ANG1005 trial, and no further studies are planned in the glioma setting with this compound.

Background: In the malignant brain tumor sonic hedgehog medulloblastoma (SHH-MB) the properties of cancer cells are influenced by their microenvironment, but the nature of those effects and the phenotypic consequences for the tumor are poorly understood. The aim of this study was to identify the phenotypic properties of SHH-MB cells that were driven by the nonmalignant tumor microenvironment.

Methods: Human induced pluripotent cells (iPSC) were differentiated to cerebellar organoids to simulate the nonmaliganant tumor microenvironment. Tumor spheroids were generated from 2 distinct, long-established SHH-MB cell lines which were co-cultured with cerebellar organoids. We profiled the cellular transcriptomes of malignant and nonmalignant cells by performing droplet-based single-cell RNA sequencing (scRNA-seq). The transcriptional profiles of tumor cells in co-culture were compared with those of malignant cell monocultures and with public SHH-MB datasets of patient tumors and patient-derived orthotopic xenograft (PDX) mouse models.

Results: SHH-MB cell lines in organoid co-culture adopted patient tumor-associated phenotypes and showed increased heterogeneity compared to monocultures. Subpopulations of co-cultured SHH-MB cells activated a key marker of differentiating granule cells, NEUROD1 that was not observed in tumor monocultures. Other subpopulations expressed transcriptional determinants consistent with a cancer stem cell-like state that resembled cell states identified in vivo.

Conclusions: For SHH-MB cell lines in co-culture, there was a convergence of malignant cell states towards patterns of heterogeneity in patient tumors and PDX models implying these states were non-cell autonomously induced by the microenvironment. Therefore, we have generated an advanced, novel in vitro model of SHH-MB with potential translational applications.

Background: Fully automatic skull-stripping and tumor segmentation are crucial for monitoring pediatric brain tumors (PBT). Current methods, however, often lack generalizability, particularly for rare tumors in the sellar/suprasellar regions and when applied to real-world clinical data in limited data scenarios. To address these challenges, we propose AI-driven techniques for skull-stripping and tumor segmentation.

Methods: Multi-institutional, multi-parametric MRI scans from 527 pediatric patients (n = 336 for skull-stripping, n = 489 for tumor segmentation) with various PBT histologies were processed to train separate nnU-Net-based deep learning models for skull-stripping, whole tumor (WT), and enhancing tumor (ET) segmentation. These models utilized single (T2/FLAIR) or multiple (T1-Gd and T2/FLAIR) input imaging sequences. Performance was evaluated using Dice scores, sensitivity, and 95% Hausdorff distances. Statistical comparisons included paired or unpaired 2-sample t-tests and Pearson's correlation coefficient based on Dice scores from different models and PBT histologies.

Results: Dice scores for the skull-stripping models for whole brain and sellar/suprasellar region segmentation were 0.98 ± 0.01 (median 0.98) for both multi- and single-parametric models, with significant Pearson's correlation coefficient between single- and multi-parametric Dice scores (r > 0.80; P < .05 for all). Whole tumor Dice scores for single-input tumor segmentation models were 0.84 ± 0.17 (median = 0.90) for T2 and 0.82 ± 0.19 (median = 0.89) for FLAIR inputs. Enhancing tumor Dice scores were 0.65 ± 0.35 (median = 0.79) for T1-Gd+FLAIR and 0.64 ± 0.36 (median = 0.79) for T1-Gd+T2 inputs.

Conclusion: Our skull-stripping models demonstrate excellent performance and include sellar/suprasellar regions, using single- or multi-parametric inputs. Additionally, our automated tumor segmentation models can reliably delineate whole lesions and ET regions, adapting to MRI sessions with missing sequences in limited data context.

Background: To improve survival in patients with high-grade glioma, INC280 (capmatinib) a highly selective and potent oral inhibitor of the MET receptor with robust central nervous system (CNS) penetration, was evaluated in combination with bevacizumab (BEV).

Methods: There were 2 phases, dose-escalation (3+3 design) and dose-expansion, which included patients (1) who progressed during or after first-line therapy (no prior BEV), (2) who progressed during or after second-line therapy with BEV, and (3) who had unresectable high-grade glioma (no prior BEV).

Results: Sixty-four patients with high-grade glioma were treated; 18 in escalation cohorts and 46 in expansion Cohorts A (21), B (15), and C (10). The maximum-tolerated dose (MTD) was not reached and the RP2D was 400 mg capmatinib PO BID (800 mg daily). Treatment continued for a median of 14 weeks and up to ~6 years in one patient. Common treatment-related adverse events (65% ≤ Grade 2) included fatigue, peripheral edema, nausea, diarrhea, ALT increased, and constipation. Headaches and seizures occurred in 11 patients; Grade 3+ events included Grade 3 headache (1) and Grade 3 seizures (4). There were no treatment-related deaths. The 12 responders to treatment (2 CRs [1 pt in escalation and 1 pt in Cohort A] and 10 PRs [2 pts in escalation and A = 6, B = 1, and C = 1]) had a median duration of response of 9.2 months. Two patients with durable responses (CR >5 years, PR >1 year) did not harbor baseline c-MET alterations.

Conclusion: Capmatinib + BEV was well-tolerated but had no clear signal of activity in c-MET non-activated high-grade glioma.

Background: Central nervous system (CNS) metastases are a significant health challenge, particularly in Africa. This study evaluates the preclinical characteristics, primary causes, management strategies, and outcomes of CNS metastases in Africa.

Methods: A systematic review of the literature was conducted using PubMed, Google Scholar, and Web of Science following PRISMA guidelines to identify studies on CNS metastases in Africa.

Results: Thirty-one articles were reviewed, including 28 retrospective studies and 3 case reports. The retrospective studies comprised 12 552 patients, with 681 (5.42%) diagnosed with CNS metastases. Nigeria reported the highest number of cases (323), followed by Tunisia (180). The mean patient age was 48.20 years (range: 44.48-51.93), with a higher proportion in women (69.97%, 95% confidence interval [CI]: 54.59-85.35). Common symptoms were headaches (44.87%, 95% CI: 20.76-68.97) and motor deficits (21.39%, 95% CI: 6.40-36.38). Diagnostic tools included MRI (38.27%, 95% CI: 18.08-58.47) and CT (51.28%, 95% CI: 29.13-73.42). The most common primary tumor sites were breast (41.33%, 95% CI: 24.87-57.79) and lung (14.85%, 95% CI: 4.90-24.79). Treatment strategies involved surgery (62.01%, 95% CI: 33.01-91.01), radiotherapy (68.97%, 95% CI: 41.31-96.63), and chemotherapy (60.72%, 95% CI: 32.95-88.50). Outcomes included improved disease status in 34.99% (95% CI: 13.92-56.07), mortality in 44.88% (95% CI: 20.88-68.89), and loss to follow-up in 1.83% (95% CI: 0-3.72).

Conclusion: CNS metastases in Africa show a higher proportion in women, with breast and lung cancers as the primary sources. Improved diagnostic and treatment strategies are essential to better patient outcomes.

Background: Survival of pediatric and young adults with malignant glioma remains poor despite progress in treatment. This is especially true for diffuse hemispheric glioma (DHG), H3 G34-mutant, which is often present in adolescent and young adult patients. This scoping review consolidates existing knowledge of DHG H3 G34-mutant and identifies future targets and therapeutic options. By streamlining this information, we aim to elucidate knowledge gaps in the field to better inform the community and motivate future research efforts.

Methods: In October 2024, MEDLINE, Embase, Cochrane Library, and Web of Science Core Collection were searched. Two reviewers screened all articles by title and abstract review and 3 independent reviewers extracted all studies meeting inclusion criteria relevant to H3G34R/V tumors (preclinical and clinical studies).

Results: Of the 2203 articles screened, 220 were deemed eligible (79 literature reviews, 7 systematic reviews, 63 preclinical studies, and 71 clinically oriented studies). We found that the United States and Acta Neuropathologica were the top country and journal contributors, respectively.

Conclusion: For this disease, it is critical to the field to conduct further research related to complexities of the tumor microenvironment, translation of preclinical studies to therapeutic early phase trials, and determining the role of targeted central nervous system drug delivery, so as to improve disease prognosis and survival.

Background: Glioblastoma (GBM) treatment is hindered by a dearth of representative mouse GBM preclinical models in immunocompetent mice. Here, we characterized 5 murine GBM stem-like cell (mGSC) models derived from lentivirus-induced tumors in transgenic mice that are driven by the activation of the Nf1-Ras signaling pathway and inactivation of Tp53.

Methods: MGSC lines (005, RIG, NF53, C1, and C3) were cultured as spheres in serum-free stem cell media. Whole exome sequencing (WES) was employed to quantify single nucleotide polymorphisms (SNPs). Stem cell properties were characterized by stemness in vitro and tumorigenicity after intracerebral implantation in C57BL/6 mice. Tumor phenotypes and the immune microenvironment were characterized by immunohistochemistry, flow cytometry, and RNA sequencing.

Results: WES revealed a large variation in coding sequence SNPs across mGSC lines (~20-fold), likely influenced by the mixed backgrounds of the parental mice. MGSCs exhibited variable clonogenic sphere formation and CD133 expression levels. In vivo, they consistently initiated lethal malignant gliomas, with median survival ranging from 29 to 82 days, and showed strong CD44 expression and variable invasiveness. The tumor microenvironment featured an abundance of CD68+ macrophages and uniform high PD-L1+ myeloid cells, while T-cell infiltration varied among the models, with low mutation burden C1 and C3 exhibiting fewer tumor-infiltrating T cells.

Conclusions: Upon orthotopic implantation in immunocompetent mice, mGSCs generate tumors characteristic of human GBM. Despite similar strategies to generate these mGSCs, they exhibited a range of phenotypes and immune profiles in mGSC-derived orthotopic tumors. These mGSCs provide new preclinical GBM models for developing GBM immunotherapies.