Neuro-oncology advances最新文献

Background: Glioblastoma represents one of the most aggressive and fatal primary brain tumors in adults. Chemotherapeutic agents, while integral to management, frequently induce varying levels of myelotoxicity. The aim is to investigate the clinical impact of myelotoxicity in patients treated with the CeTeG versus the Stupp regimen which has not yet been systematically investigated under real-world conditions.

Methods: This retrospective study included patients with newly diagnosed glioblastoma who underwent radiochemotherapy. Peripheral blood counts were systematically assessed throughout first-line therapy, starting at the initiation of radiation and continuing until either first disease progression or death, whichever occurred earlier.

Results: Among 161 identified patients, 133 (83%) were assigned to the myelotoxicity cohort and 28 (17%) to the non-myelotoxicity cohort. Female sex was independently associated with a higher incidence of myelotoxicity (p = 0.007). In multivariate analysis leukopenia ≥ grade 2 was significantly associated with improved progression-free and overall survival in both the overall and CeTeG cohorts. Neutropenia ≥ grade 2 similarly correlated with improved survival outcomes in the overall cohort. Prophylaxis against pneumocystis jiroveci pneumonia was associated with a significant survival advantage in both the overall and Stupp cohorts, as was lymphopenia grade 3-4.

Conclusion: Myelotoxicity at the time of glioblastoma diagnosis does not seem to be detrimental to patient outcomes. Our findings highlight the importance of pneumocystis jiroveci prophylaxis in the Stupp regimen. This raises the intriguing question of whether future chemotherapy dosages could be tailored based on individual blood values, potentially exceeding current standard doses. Prospective studies are needed to explore these possibilities, including the feasibility of high-dose therapies similar to those used in leukemia treatment.

Background: Glioblastoma (GBM) prognosis remains poor, and although immune checkpoint inhibitors (ICI) have transformed the treatment of many tumors, they are ineffective in GBM. However, response to ICIs occurs in high-tumor-mutational-burden (TMB) GBMs. To address the immunological impact of high TMB in GBM, we created a high TMB syngeneic mouse model from the low TMB SB28 GBM cell line.

Methods: We used CRISPR-Cas9 to target murine Msh2, Mlh1, CXCL10, and CCL5. Single-cell-sorted clones were characterized by whole exome, bulk RNA-sequencing, and neoantigen prediction. Clones were injected subcutaneously or intracranially with or without anti-PD-1/anti-CTLA4 and dexamethasone.

Results: Loss of mismatch repair (MMR) proteins Msh2 or Mlh1 increased nonsynonymous mutations. A fraction of mice with intracranial Msh2KO but not Mlh1KO SB28 showed long-term survival with anti-PD-1/anti-CTLA4 treatment plus dexamethasone. Long-term surviving mice from Msh2 KO SB28 rejected rechallenged subcutaneous tumors. Subcutaneous tumors from clones with increased TMB grew more slowly. This was fully abrogated in Rag1 null mice for Msh2KO but only partially for Mlh1KO SB28. Hypermutant Msh2KO clones spontaneously secreted CXCL10, CCL5, and increased pro-inflammatory chemokines after IFN-γ stimulation. Knockout of CXCL10 or CCL5 in the highest TMB Msh2KO clone restored flank tumor growth, indicating loss of immune response despite elevated TMB.

Conclusion: Mismatch repair-deficient SB28 tumors were more immunogenic, but this was not completely correlated with TMB. Rather, rejection depended on increased secretion of pro-inflammatory chemokines. Msh2 and Mlh1 loss was not equivalent, suggesting that additional studies are needed to elucidate germline and somatic mismatch repair gene-specific immune alterations.

Background: The intra- and inter-tumoral heterogeneity of glioblastoma (GBM) represents a significant therapeutic challenge and barrier to the generation of reliable and accurate models for in vitro studies. Three-dimensional models, such as patient-derived neurospheres (PDN) and organoids (PDO), recapitulate complex cellular states. However, the direct comparison of models derived in parallel from the same primary tumor tissue has never been performed. The aim of this study was to determine the tumor cell composition of PDN and PDO models relative to matched primary GBM tissue.

Methods: Four GBM surgical samples were used to establish matched PDO and PDN models, which were genomically verified using single nucleotide polymorphism array. DNA methylation, histology, and transcriptome were examined for intra-tumoral heterogeneity correlating with the matched GBM tissue. PDN lines were used to investigate the tumor cell composition response to temozolomide chemotherapy over time, maximizing their utility.

Results: We find that both patient-derived models recapitulate the genomic, epigenomic, and tumor cell heterogeneity of the primary tissue at similar capacity. Furthermore, single-nuclei RNA sequencing revealed a subset of organoids containing small numbers of non-malignant cells from neuron and immune cell lineages. Harnessing the intra-tumoral heterogeneity of PDN models, we reveal the impact of temozolomide chemotherapy on individual cell states, altering composition of tumors over time in response to treatment.

Conclusions: Our data confirms that both PDN and PDO patient-derived models recapitulate patient intra-tumoral heterogeneity providing a platform for tumor cell state refined therapeutic studies.

Abstract: BackgroundStudies suggest that high intensities of tumor treating fields (TTFields) correlate with prolonged survival in newly diagnosed glioblastoma. However, no randomized clinical studies have tested different doses of TTFields, and the treatment remains controversial for recurrent glioblastoma. This study examined the clinical efficacy of dose-enhanced TTFields in first recurrence glioblastoma (rGBM).

Methods: This open-label, randomized, multicenter, phase 2 clinical trial was conducted nationwide in Denmark (2020-2024) with planned enrollment of 84 rGBM patients. Inclusion criteria were focal disease, KPS ≥ 70, and eligibility for resection. Patients were randomized (1:1) to receive standard or dose-enhanced TTFields in addition to standard-of-care. Dose enhancement (25%-70%) in the tumor was achieved by placing five small cranial burr holes over the tumor bed with overlapping TTFields transducer arrays. The primary outcome was the overall survival (OS) rate at 12 months (OS12). Secondary outcomes included progression-free survival, toxicity, steroid use, objective response rate (ORR), and quality of life.

Results: We enrolled 58 participants with a mean (SD) age of 59.2 (11.1) years and a median (IQR) KPS of 90 (10). Preplanned interim analysis of the first 52 patients resulted in early trial termination due to futility. Intent-to-treat analysis of the complete cohort showed an OS12 of 56% vs 46% (P = .38) and a median OS of 12.3 vs 11.1 months (P = .93) for intervention and control, respectively. Differences in the secondary outcomes were insignificant.

Conclusion: Dose-enhanced TTFields utilizing burr holes over the resection cavity were not associated with improved survival in rGBM, with low study power as the primary limitation.

Background: Lysine-specific demethylase 1 (LSD1) is overexpressed in glioblastoma, contributing to tumor growth and treatment resistance. LSD1 inhibitors have shown preclinical promise but have had limited clinical development for glioblastoma. Given the frequent kinase pathway alterations seen in glioblastoma, the interplay between LSD1 inhibition and kinase signaling pathways was investigated.

Methods: Glioblastoma stem cell (GSC) lines and normal human astrocytes (NHAs) were treated with catalytic LSD1 inhibitors, NCD38 and bomedemstat, and the LSD1 scaffolding inhibitor, seclidemstat alone and in combination with kinase inhibitors, including osimertinib, afatinib, and ulixertinib. The effect on cell viability, proliferation, and neurosphere formation was assessed, and synergy scores were calculated using Bliss synergy models. Kinase signaling was analyzed and in vivo efficacy was evaluated in orthotopic xenograft models.

Results: LSD1 knockdown and seclidemstat reduced kinase signaling, while catalytic LSD1 inhibitors increased kinase activity or had no effect. Catalytic LSD1 inhibitors combined with kinase inhibitors, synergistically reduced GSC viability and proliferation while sparing NHAs. Combination treatment consistently reduced phospho-S6 ribosomal protein levels in three different GSC lines, and basal phospho-S6 ribosomal protein levels across the GSCs and the NHAs were negatively correlated with a synergistic response. The generation of an NCD38-resistant GSC showed increased kinase activity and was associated with enhanced osimertinib sensitivity. Combined treatment with NCD38 and osimertinib in glioblastoma-bearing mice delayed tumor growth and improved survival outcomes.

Discussion: These findings provide a rationale for further investigation of combination therapies of catalytic inhibitors of LSD1 and EGFR and dual-targeted inhibitors to overcome resistance and improve outcomes.

Abstract: BackgroundGlioblastoma (GBM) is an aggressive brain tumor. The authors of this study wanted to find out whether areas of reduced blood flow, called ischemia, that appear after surgery affect how long people live with this disease. To do this, they reviewed scans from 451 patients taken within three days after tumor removal and measured the size of any new areas with poor blood supply. Their results showed that larger areas of ischemia were linked to shorter survival. The prognostic relevance of postoperative ischemia in GBM remains unclear. This study investigated the association between infarct volume and survival in patients with Isocitrate Dehydrogenase (IDH)-wildtype GBM.

Methods: We retrospectively reviewed 451 patients with IDH-wildtype GBM who underwent resection between 2013 and 2024 and had diffusion-weighted imaging within 72 h postoperatively. Ischemic changes were defined as new areas of diffusion restriction and stratified into none/rim-only, small (<5 cm³), and large (≥5 cm³) infarcts. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier and Cox regression models adjusted for age, preoperative KPS, tumor size, extent of resection, MGMT status, adjuvant therapy, and postoperative deficits.

Results: Large infarcts were associated with shorter median PFS (7.0 months [95% CI: 5-9]) and OS (14.0 months [95% CI: 9-18]) compared to small infarcts and none/rim-only (PFS: P = .07; OS: P = .001). In multivariable models, infarct volume was independently associated with reduced OS (per cubic centimeter increase, HR = 1.02, 95% CI: 1.01-1.032; P = .003), while its association with PFS did not reach statistical significance (HR = 1.01, 95% CI: 1.0-1.02; P = .13). When modeled categorically, large infarcts remained predictive of shorter PFS (HR = 1.4, 95% CI: 1.01-1.9; P = .04) and OS (HR = 1.7, 95% CI: 1.2-2.4; P = .001).

Conclusions: Infarct volume is independently associated with survival in IDH-wildtype GBM. These findings highlight the clinical relevance of postoperative ischemia and may point toward ischemia-related mechanisms as targets for future therapeutic investigation.

Background: The impact of systemic therapy (ST) on outcomes for patients with brain-only metastases (BrM) in the absence of extracranial disease (ECD) is not well established. We compared outcomes between patients with BrM treated with stereotactic radiosurgery (SRS) who received ST ≤3 months (mos), >3 mos, or not at all after SRS.

Methods: We identified BrM patients who completed SRS across two institutions from 1/2015 to 12/2020. Intracranial progression after SRS was determined by brain MRI radiographic recurrence. Overall survival (OS) and intracranial progression free survival (iPFS) estimates were also generated.

Results: In total, 342 patients with BrM were identified. Primary sites included lung (73%), breast (12%), and additional sites (15%). Almost half, 169 (49%), received no ST, 80 (23%) received ST ≤3 mos, and 93 (27%) received ST >3 mos after SRS. Median age was younger in the ST >3 mos cohort (60.5years) compared with ST <3mo (67.7years) and no ST (67.0years), P = .0002. Median OS differed significantly between groups: ST ≤3 mos with 24.9mos (95%CI: 16.6-51.1), ST >3 mos with 27.5mos (95% CI: 20.6-37.5), and no ST with 11.0mos (95%CI: 9-17.5), P = .002. Median iPFS differed significantly between groups: ST ≤3 mos 16.1mos (95% CI: 9.5-33.7), ST >3 mos 8.9mos (95% CI: 6.9-13.5), and no ST 10.0mos (95% CI: 6.7- 15.1). However, timing of ST was not significant multivariate analysis.

Conclusions: In our cohort of BrM patients, ST after SRS improves OS regardless of timing. ST ≤3 mos may improve iPFS compared with ST >3 mos after SRS, which warrants further investigation. Appropriate patients with BrM should be referred for a multi-disciplinary discussion of ST following SRS.

Background: Brain metastasis is the most ominous form of cancer relapse. There is urgent need to develop preclinical mouse models to study brain metastasis and new therapeutic strategies. Patient derived xenograft (PDX) models are clinically relevant mouse models. The brain stromal cells play critical roles on metastatic initiation and outgrowth. We have shown that PPARγ signaling in cancer cells is activated by astrocytes to increase brain metastatic outgrowth. Here, we aim to compare ectopic and orthotopic brain metastasis PDX models to address whether the unique brain microenvironment affects therapeutic efficacy of PPARγ antagonist.

Methods: A collection of surgically resected brain metastasis tissues from cancer patients were used to generate PDX models. Ectopic and orthotopic brain metastasis PDX models were generated and characterized. The tumor growth was tracked in both PDX models when treated with PPARγ antagonist.

Results: The growth rate of PDX tumors increased over passages in our ectopic PDX models and maintains in the orthotopic PDX models. Brain stromal cells were absent in the ectopic PDX tumors. Brain metastasis cancer cells sustained the PPARγ expression in both ectopic and orthotopic PDX tumors, at the similar level as the original brain metastasis tissues. However, PPARγ antagonist only decreased tumor growth in the brain without affecting subcutaneous tumors.

Conclusions: Our results show that PDX models are successfully generated from clinical brain metastasis tissues and maintain the molecular characteristics in the brain metastasis cancer cells. Moreover, our study indicates the importance of the brain microenvironment to the therapeutic response in brain metastasis.

Abstract: BackgroundDespite intensive therapies, outcomes for high-risk pediatric brain tumors (PBTs) remain dismal, prompting the search for novel treatments. DNA methyltransferase inhibitors (DNMTi) have been shown to prime tumors to improve response to checkpoint inhibition. The aim of this study was to investigate the potential of decitabine (DAC), in combination with a PD-1 inhibitor, to improve survival in pediatric high-risk brain tumor models.

Methods: Analysis of human PBT datasets was performed to determine gene expression levels of immune cell markers. Tumor response to DAC, with or without a PD-1 inhibitor, was tested in murine models representing H3-wildtype diffuse intrinsic pontine glioma (DIPG), H3K27-mutant diffuse midline glioma (DMG), atypical teratoid rhabdoid tumor (ATRT), and medulloblastoma (MB). CyTOF analysis of allograft tumors was performed to characterize changes within the tumor microenvironment.

Results: Analysis of PBT subtypes revealed heterogeneous expression of immune cell markers, checkpoint receptors, and MHC molecules. DAC treatment decreased DNA methylation and increased neoantigen expression in human and mouse tumor cells. DAC treatment resulted in prolonged survival in syngeneic mouse models of DIPG and ATRT but not DMG and MB models. However, no added survival benefit was observed when combined with a PD-1 inhibitor. CyTOF analysis of mouse tumors revealed changes in local immune cell infiltration.

Conclusions: DAC alone or in combination with a checkpoint inhibitor can alter the immune microenvironment in mouse tumor models. Changes were observed in H3-wildtype DIPG and ATRT models, suggesting that certain tumor subtypes may respond to immune priming with DNMTi.