Journal of Neuro-Oncology最新文献

Background: Global comparisons of the burden and impact of cancers of the brain and central nervous system (CNS) are critical for developing effective control strategies and generating etiological hypotheses to drive future research.

Methods: National incidence estimates were obtained from GLOBOCAN 2022, and recorded incidence data from the Cancer in Five Continents series, both developed and compiled by the International Agency for Research on Cancer. We examined the estimated age-standardized incidence rates in 185 countries, as well as time trends in recorded incidence in 35 countries, quantifying the direction and change in the magnitude of the rates using the estimated average percentage change (EAPC).

Results: In 2022, 322,000 new cases of brain and CNS tumors were estimated globally. By world region, the highest incidence rate was seen in Northern America (5.46 per 100,000), Eastern Asia (3.95), and Western Europe (5.56). Africa had relatively lower incidence rates. By country and age group, Austria and the U.S. exhibited the highest rates in boys (3.5 in both), while in adolescents and young adults (AYA), Norway had the highest incidence rates in both males (4.7) and females (3.8). Among adults (+ 40yo), the highest rates in males were observed in the Northern European countries of Norway (18.6), Lithuania (18.4), and Latvia (16.7). In terms of time trends, incidence rates tended to be rather stable in most world regions over the last decade, though increases were observed in selected countries. Trends-based predictions indicate that if incidence rates remain stable, population ageing and growth would mean there would be 474,000 new cases by the year 2045, a 47% increase from 2022.

Conclusion: While the increased incidence rates in certain populations require further study, the future predictions based on stable rates to 2045 are of particular concern, with a close to 50% increase in the number of brain and CNS cancer patients expected over the coming decades. A global 2% decline in rates would be needed to ensure the future brain and CNS cancer burden does not exceed present levels.

Background: Glioblastoma (GBM) demonstrates extensive immunomodulatory mechanisms that challenge effective therapeutic interventions. These phenomena extend well beyond the tumor microenvironment (TME) and are reflected in the circulating immunophenotype. B lymphocytes (B cells) have received limited attention in GBM studies despite their emerging importance in mediating both local and systemic immune responses. Recent findings highlight the complex regulatory interactions between B cells and other immune cell populations, including tumor-infiltrating macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and other infiltrating lymphocytes (TILs). B cells are believed to hinder the efficacy of modern immunotherapy strategies focusing on T cells.

Methods: This is a focused review of available evidence regarding B cells in GBM through January 2025.

Results: Peripheral blood reflects a systemically dampened immune response, with sustained lymphopenia, increased plasma cells, and dysfunctional memory B cells. The tumor immune landscape is enriched in cells of B-lineage. Subsets of poorly characterized B regulatory cells (Bregs) populate the TME, developing their phenotype due to their proximity to MDSCs, TAMs, and tumoral cells. The Bregs inhibit CD8⁺ T activity and may have potential prognostic significance.

Conclusion: Understanding the role of B cells, how they are recruited, and their differentiation shifted towards an immunomodulatory role could inform better therapeutic strategies and unleash their full antitumoral potential in GBM.

Purpose: We aimed to expand and refine the experimental models for pediatric-type diffuse high grade gliomas (pHGG) and the methods to follow up disease progression in mouse pHGG xenografts.

Methods: Using whole exome sequencing and immunoassays we characterized pHGG primary cultures and xenografts established at hospital SJD Barcelona. We obtained tumor samples and serial CSF samples from mouse xenografts. To assess tumor progression, we evaluated: (1) mouse weight, (2) human cell counts in brain paraffin sections, and (3) tumor DNA amount, quantified through droplet digital polymerase chain reaction (ddPCR) in paraffin sections and cerebrospinal fluid (CSF).

Results: We established 15 experimental models of three pHGG subclasses, four of which engrafted in mice. Xenografts HSJD-DIPG-007 and HSJD-DMG-005 are diffuse midline glioma (DMG) H3 K27-altered, HSJD-GBM-002 is an H3 G34-mutant diffuse hemispheric glioma, and HSJD-GBM-001 is an H3-wildtype and IDH-wildtype pHGG. ddPCR quantification of human H3F3A K27M, H3F3A G34R, and ACVR1 R206H in paraffin samples is linear and sufficiently sensitive. We required a preamplification step to detect H3F3A K27M in CSF. In HSJD-DIPG-007 xenografts, human cell counts correlated with H3F3A amounts in paraffin for the whole engraftment period. Weight loss correlated with human cell counts and H3F3A amounts in paraffin. Serial collection of CSF was feasible, but H3F3A amounts in the CSF correlated only with weight loss.

Conclusion: The developed methods contribute to the preclinical field of pHGG and introduce for the first time the concept of liquid biopsy in mice, which still needs improvement regarding its use as a preclinical biomarker.

Purpose: To investigate the molecular mechanisms underlying resistance to dopamine agonists (DA).

Methods: LC-MS/MS analysis was performed on rat pituitary neuroendocrine tumors (PitNET) cell line GH3 to identify differentially expressed proteins induced by cabergoline (CAB) treatment. A total of 180 human PITNET samples were subjected to transcriptome analysis. Immunohistochemistry (IHC) was conducted on 29 tumor samples to validate NDFIP1 alteration. A xenograft mouse model was established by subcutaneously injecting GH3 cells, with or without NDFIP1 overexpression, into nude mice to investigate tumor growth. PitNET cell lines were treated with CAB. Cell proliferation was assessed using the CCK-8, and protein expression levels were examined through Western blot analysis.

Results: CAB treatment upregulated FDFT1 and NDFIP1 protein expression in GH3 cells, with NDFIP1 showing a significant positive correlation with tumor size, as confirmed by IHC results. MMQ and GH3 cells overexpressing NDFIP1 exhibited enhanced viability and reduced sensitivity to CAB. In vivo experiments demonstrated that subcutaneous injection of NDFIP1-overexpressing GH3 cells led to enhanced tumor growth compared to parental GH3 cells. Although the total levels of PTEN remained unaltered, NDFIP1 overexpression induced PTEN nuclear translocation, potentially activating the mTOR pathway. This was supported by increased phosphorylation of key mTOR pathway components, including p-AKT and p-4EBP1, in cells overexpressing NDFIP1.

Conclusion: CAB treatment induces the upregulation of NDFIP1 in PitNET cells, which correlates with tumor size and contributes to reduced CAB sensitivity, potentially through activation of the mTOR pathway. NDFIP1 as a potential therapeutic target for overcoming DA resistance in PitNET patients.

Background: Pregnancy's impact on cancer has been understudied throughout the literature. The current authoritative cancer database in the US, NCI's SEER database, tracks nearly all aspects of cancer care however has no provision to track pregnancy. Consequently, there are no systematic evidence based clinical guidelines available for this vulnerable population.

Objective: This retrospective cohort study outlines reported clinical presentation, obstetric outcomes, and treatment regimens for pregnant patients diagnosed with glioma to better understand current practice pattern for glioma during pregnancy.

Evidence review: An exhaustive PubMed and Cochrane based literature search was performed for pregnancy and glioma. Individual patient data was extracted primarily from case reports and case series, since pregnancy is an exclusion criterion for most clinical trials.

Findings: We identified a cohort of 94 patients, 54% of whom (n = 51/94) were diagnosed prior to their pregnancy. Of the patients who were diagnosed during their pregnancy, diagnosis was most common in the second trimester (27%, n = 25/94). Seizure was the most common presenting symptom and maternal survival varied significantly by glioma grade. Treatment delays were common and were most detrimental to maternal survival in glioblastoma (GBM) (22 months (no delay) vs 8 months (delay) p < 0.10). Most patients regardless of tumor grade delivered healthy babies (80%, n = 75/94) while GBM carried the highest rate of birth complications or defects (15% n = 3/20). Fetal exposure to chemotherapy and/or radiotherapy increased the rate of birth defects or complications from 5% (n = 2/47) to 16% (n = 6/37).

Conclusions and relevance: In summary, we found wide practice variation in management of glioma during pregnancy. Systematic reporting on this vulnerable population is needed to better serve mothers and fetuses during this incredibly challenging life event.

Purpose: Immune checkpoint inhibitors (ICI) are increasingly being administered to cancer patients, including those with brain metastases (BMs). However, in a subset of cancer patients, ICI have shown to paradoxically accelerate tumor growth. This phenomenon is known as hyperprogressive disease (HPD). The aim of this study is to investigate the occurrence of HPD following initiation of ICI in BM patients.

Methods: We retrospectively reviewed the charts of 60 surgically treated patients with BMs from non-small cell lung cancer or melanoma who were administered ICI at the Brigham and Women's Hospital, Boston between July 2008 and July 2018. BM tumor volumes before and after initiation of ICI were collected. HPD was defined as a 'post-immunotherapy' tumor growth rate (TGR) > 2 times 'pre-immunotherapy' TGR within three months following initiation of ICI.

Results: Among the 25 included patients treated with ICI, five patients showed HPD with an increase of post-immunotherapy TGR ranging from 4.9 to 207.7 times the pre-immunotherapy TGR. The median survival after initiation of ICI was was 8.0 months in the HPD cases and 13 months in the non-HPD patients.

Conclusion: HPD occurred in about 20% of BM patients receiving ICI. More research is necessary to prospectively analyze the occurrence of HPD and identify predictive factors for HPD in BM patients.

Purpose: Advances in multidisciplinary treatment of childhood brain tumors have significantly prolonged survival and reduced treatment-related complications. This makes the accessibility of digital neurocognitive assessment an important issue in the post-pandemic era.

Methods: Twenty pediatric brain tumor patients were recruited between August 2023 and August 2024, and a total of eight standardized Cambridge Neuropsychological Test Automated Battery (CANTAB) tests targeting executive function, memory, and attention were applied on a digital system. Subjects with test data exceeding the 5th and 95th percentile ranges were defined as outlier in this context. Three domains (DMS, PAL, SWM) of the normative data for adult patients provided by CANTAB test were used for comparison. Mann-Whitney U test was used to compare differences in treatment modalities and age groups.

Results: Four patients (4/20, 20%) exhibited impairments across four to six cognitive domains, with more than 14 sub-items falling outside the 5th and 95th percentiles.Another 7 patients (7/20, 35%) had impairments confined to a single domain, even though 4 out of 7 (57%) had a total IQ above 100. The subtle neurocognitive impairment of different domains can be effectively identified by automatic digital threshold analysis and reasonably associated with clinical characteristics. The normative data provided by the CANTAB battery for adult populations further enhances the accuracy of detecting neurofunctional impairments.

Conclusion: The CANTAB test was shown to be an evaluable and user-friendly neurocognitive assessment tool for post-treatment follow-up in pediatric patients with brain tumors.

Purpose: Sonodynamic therapy, which combines a tumor cell-selective sonosensitizer with ultrasound, is gaining attention as a promising new treatment approach for glioblastoma. The objective of this case study is to report on the first applications of 5-aminolevulinic acid (5-ALA) in combination with low-intensity, non-targeted ultrasound as neo-adjuvant treatment in therapy naïve glioblastoma.

Methods: Three patients with therapy naïve newly diagnosed glioblastoma were treated once before cytoreductive surgery with 5-ALA in combination with hemispheric, low-intensity, non-targeted ultrasound, assuming cell death to be triggered by non-ablative activation of 5-ALA-induced, tumor selective porphyrins.

Results: No adverse effects were noted. Post-procedural MRI indicated a decrease in apparent diffusion coefficient values in tumors, suggesting cytotoxic effects. Relative cerebral blood volumes and leakage were increased for two patients with available perfusion imaging. Tissue obtained during surgery suggested increased cleaved-caspase III expression, a marker of apoptosis.

Conclusion: We saw an immediate marked imaging response indicating cytotoxic edema and indications of a histopathology response from just a single treatment. Correlation to clinical outcomes and extension of overall survival remains to be seen. A Phase 1 safety study has been submitted for regulatory approval.

Background: The RANO classification for glioblastoma defines resection categories based on volumetric tumor assessments, aiming to standardize outcomes related to extent of resection (EOR). This study revalidates the prognostic impact of RANO classes by reconstructing individual patient data (IPD).

Methods: A systematic review and meta-analysis were performed, including three studies comprising 580 glioblastoma patients. Included studies reported or allowed conversion to RANO classes for glioblastoma resection extent, with detailed OS data and numbers at risk. Overall survival (OS) data were extracted from Kaplan-Meier survival curves, and IPD were reconstructed using Digitizelt and the R package IPDfromKM. Survival analyses were conducted using Kaplan-Meier estimates and Cox regression models.

Results: Median follow-up was 15.6 months (IQR: 10.1-28.8). Patients undergoing supramaximal resection (RANO class 1, n = 163) had the highest median OS (35.6 months; 95% CI: 30.9-40.4), significantly outperforming non-class 1 resections (median OS: 13.9 months; 95% CI: 13.0-14.7; p < 0.001). Subgroup analysis revealed superior OS for class 2a (19.0 months) over class 2b (14.1 months; p < 0.001), while class 3 and 4 resections demonstrated progressively poorer outcomes. Hazard ratios consistently favored class 1 versus all other classes (HR: 0.28; 95% CI: 0.23-0.37).

Conclusions: Supramaximal (class 1) resection provides a significant survival benefit in glioblastoma, underscoring its critical role in surgical management. The RANO classification stratifies resection outcomes effectively, supporting its use as a prognostic tool. These findings advocate for resection strategies targeting maximal tumor removal.