Neuro-oncology最新文献

Background: Medulloblastoma (MB) is one of the most common malignant brain tumors in children. Current preclinical in vivo model systems for MB have increased our understanding of molecular mechanisms regulating MB development. However, they may not be suitable for large-scale studies. The aim of this study was to investigate if a zebrafish-based xenograft model can recapitulate MB growth and enable rapid drug testing.

Methods: Nine different MB cell lines or patient-derived cells were transplanted into blastula-stage zebrafish embryos. Tumor development and migration were then monitored using live imaging. RNA sequencing was performed to investigate transcriptome changes after conditioning cells in a neural stem cell-like medium. Furthermore, drug treatments were tested in a 96-well format.

Results: We demonstrate here that transplantation of MB cells into the blastula stage of zebrafish embryos leads to orthotopic tumor growth that can be observed within 24 h after transplantation. Importantly, the homing of transplanted cells to the hindbrain region and the aggressiveness of tumor growth are enhanced by pre-culturing cells in a neural stem cell-like medium. The change in culture conditions rewires the transcriptome toward a more migratory and neuronal phenotype, including the expression of guidance molecules SEMA3A and EFNB1, both of which correlate with lower overall survival in MB patients. Furthermore, we highlight that the orthotopic zebrafish MB model has the potential to be used for rapid drug testing.

Conclusions: Blastula-stage zebrafish MB xenografts present an alternative to current MB mouse xenograft models, enabling quick evaluation of tumor cell growth, neurotropism, and drug efficacy.

Significant gaps remain in our understanding of immunotherapy-related neurotoxicity in pediatric patients, largely because much of our knowledge comes from studies in adults. Accurately identifying the adverse effects of immunotherapy in children is also challenging, owing to variations in terminology and grading systems. Moreover, the manifestation of immunotherapy-related neurotoxicity differs greatly across different diseases, various modalities, dosages, and delivery methods. Combining immunotherapy with other treatments might improve outcomes but introduces new complexities and potential for increased toxicities. Additionally, pediatric patients with intracranial malignancy have unique responses to immunotherapies and distinct neurotoxicity compared to those with extracranial malignancy. Consequently, we must enhance our understanding of the pathophysiology, prevalence, severity, and management of immunotherapy's neurotoxic effects in this vulnerable group. This review consolidates the current knowledge of immunotherapy-related neurotoxicity in pediatric oncology, highlighting various types of neurotoxicity including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and tumor inflammation-associated neurotoxicity (TIAN), among others. Furthermore, we examine the unique features of neurotoxicity associated with adoptive cellular therapy (ACT), antibody-based therapies, immune checkpoint inhibitors (ICIs), oncolytic viruses (OV), and cancer vaccines.

Background: Glioblastoma (GBM) is an aggressive form of brain cancer in which treatment is associated with toxicities that can result in therapy discontinuation or death. This analysis investigated clinical and genetic markers of vascular toxicities in GBM patients during active treatment.

Methods: In total, 591 non-Hispanic White GBM patients with clinical data were included in the analysis from NRG RTOG-0825. Genome-wide association studies (GWAS) were performed from genotyped blood samples (N = 367) by occurrence of thrombosis or hypertension (grade ≥ 2). A clinical prediction model was produced for each vascular toxicity. Significant GWAS variants were then added to the clinical model as a single nucleotide polymorphism (SNP)-dose-effect variable to produce the final genetic models.

Results: Thrombosis and hypertension were experienced by 62 (11%) and 59 (10%) patients, respectively. Patients who experienced hypertension displayed improved survival over those without hypertension (median overall survival: 25.72 vs. 15.47 months, p = 0.002). The genetic model of thrombosis included corticosteroid use (odds ratio [OR]: 7.13, p = 0.02), absolute neutrophil count (OR: 1.008, p = 0.19), body surface area (OR: 18.87, p = 0.0008), and SNP-dose effect (3 variants; OR: 3.79, p < 0.0001). The genetic model of hypertension included bevacizumab use (OR: 0.97, p = 0.95) and the SNP-dose effect (6 variants; OR: 4.44, p < 0.0001).

Conclusions: In this study, germline variants were superior in predicting hypertension than clinical variables alone. Additionally, corticosteroid use was a considerable risk factor for thrombosis. Future investigations should confirm the hazard of corticosteroid use on thrombosis and the impact of bevacizumab in other malignancies after accounting for the genetic risk of hypertension.

Background: Acquired resistance to temozolomide (TMZ) chemotherapy due to DNA mismatch repair (MMR) enzyme deficiency is a barrier to improving outcomes for isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) patients. KL-50 is a new imidazotetrazine-based therapeutic designed to induce DNA interstrand cross-links, and subsequent double-stranded breaks, in an MMR-independent manner in cells with O-6-methylguanine-DNA methyltransferase (MGMT) deficiency. Previous research showed its efficacy against LN229 glioma cells with MMR and MGMT knockdown. Its activity against patient-derived GBM that model post-TMZ recurrent tumors is unclear.

Methods: We created MMR-deficient GBM patient-derived xenografts through exposure to TMZ, followed by treatment with additional TMZ or KL-50. We also generated isogenic, MSH6 knockout (KO) patient-derived GBM and tested them for sensitivity to TMZ and KL-50.

Results: KL-50 extended the median survival of mice intracranially engrafted with either patient-derived TMZ-naïve GBM6 or TMZ-naïve GBM12 by 1.75-fold and 2.15-fold, respectively (P < 0.0001). A low dose (4 Gy) of fractionated RT further extended the survival of KL-50-treated GBM12 mice (median survival = 80 days for RT + KL-50 vs. 71 days KL-50 alone, P = 0.018). KL-50 also extended the median survival of mice engrafted with post-TMZ, MMR-deficient GBM6R-m185 (140 days for KL-50 vs. 37 days for vehicle, P < 0.0001). MSH6 KO increased TMZ IC50 for GBM6 and GBM12 cultures by >5-fold and >12-fold for cell death and live cell count outputs, respectively. In contrast, MSH6-KO actually decreased KL-50 IC50 by 10-80%.

Conclusion: KL-50-based compounds are a promising new strategy for the treatment of MGMT-deficient, MMR-deficient GBM that recurs after frontline TMZ.

Background: Pituitary adenomas (PAs) are common intracranial tumors and the TRIM family plays a crucial role in cell proliferation and therapeutic resistance of tumors. However, the role of the TRIM family in PAs is not well recognized.

Methods: CRISPR screening explored the role of the TRIM family in cell proliferation and drug resistance in PAs. In vitro and in vivo experiments were performed to evaluate the effects of Tripartite Motif Containing 21 (TRIM21). RNA-sequencing, mass spectrometry, immunoprecipitation, and ubiquitination experiments were performed to explore the molecular mechanism. NanoBiT assays were used to screen the drugs reducing TRIM21 expression.

Results: CRISPR-Cas9 screens identified that TRIM21 facilitated cell proliferation and drug resistance in PAs. Mechanistically, TRIM21 interacted with ERK1/2 through PRY-SPRY domain, leading to ERK1/2 K27-linked ubiquitination. The ERK1/2 ubiquitination promotes the interaction between ERK1/2 and MEK1/2, thereby facilitating the phosphorylation of ERK1/2. However, an excess presence of TRIM21 suppressed the phosphorylation of ERK1/2 and cell proliferation via activating ERK1/2 negative feedback pathways. Importantly, TRIM21 was upregulated in dopamine-resistant prolactinomas and cabergoline-resistant MMQ cells. Furthermore, drug screening identified that Fimepinostat and Quisinostat, can reduce the protein levels of TRIM21, inhibit tumor progression, and increase drug sensitivity.

Conclusions: TRIM21 may represent a therapeutic target for tumors, and inhibiting TRIM21 could be a potential strategy for tumor treatment.

Background: Glioblastoma (GBM), a primary malignant brain tumor, has a poor prognosis, even with standard treatments such as radiotherapy and chemotherapy. In this study, we explored the anticancer effects of the synergistic combination of perphenazine (PER), a dopamine receptor D2/3 (DRD2/3) antagonist, and temozolomide (TMZ), a standard treatment for GBM, in patient-derived human GBM tumorspheres (TSs).

Methods: The biological effects of the combination of PER and TMZ in GBM TSs were assessed by measuring cell viability, ATP, stemness, invasiveness, and apoptosis. Changes in protein and mRNA expression were analyzed using western blotting and RNA sequencing. Co-administration of PER and TMZ was evaluated in vivo using a mouse orthotopic xenograft model.

Results: The Severance dataset showed that DRD2 and DRD3 expressions were higher in tumor tissues than in the tumor-free cortex of patients with GBM. DRD2/3 knockout by CRISPR/Cas9 in patient-derived human GBM TSs inhibited cell growth and ATP production. The combined treatment with PER and TMZ resulted in superior effects on cell viability and ATP assays compared to those in single treatment groups. Flow cytometry, western blotting, and RNA sequencing confirmed elevated apoptosis in GBM TSs following combination treatment. Additionally, the combination of PER and TMZ downregulated the expression of protein and mRNA associated with stemness and invasiveness. In vivo evaluation showed that combining PER and TMZ extended the survival period of the mouse orthotopic xenograft model.

Conclusions: The synergistic combination of PER and TMZ has potential as a novel combination treatment strategy for GBM.

Background: Stereotactic radiosurgery (SRS) for patients with brain metastases (BM) is associated with a risk of distant intracranial failure (DIF). This study evaluates the impact of integrating dedicated 3D fast/turbo spin echo (3D-TSE) sequences to MPRAGE in BM detection and DIF prolongation in a histology-agnostic patient cohort.

Methods: The study population included adults treated with SRS from February 2019 to January 2024 who underwent MPRAGE alone or dual sequence with the addition of 3D-TSE starting from February 2020. Median times to DIF were estimated using the Kaplan-Meier method.

Results: The 216 study patients who underwent 332 SRS courses for 1456 BM imaged with MPRAGE and 3D-TSE (primary cohort) were compared to a control cohort (92 patients, 135 SRS courses, 462 BM). In the session-wise analysis, the median time to DIF between the cohorts was significantly prolonged in the primary vs. control cohorts (11.4 vs. 6.8 months, P = .029), more pronounced in the subgroups with 1-4 metastases (14.7 vs. 8.1 months, P = .008) and with solitary BM (36.4 vs. 10.9 months, P = .001). While patients relapsing on immunotherapy or targeted therapy did not significantly benefit from 3D-TSE (7.2 vs. 5.7 months, P = .280), those who relapsed on chemotherapy or who were off systemic therapy (including synchronous metastases) exhibited a trend toward longer time to DIF with 3D-TSE integration (14.7 vs. 7.9 months, P = .057).

Conclusions: Implementing 3D-TSE sequences into SRS practice increases BM detection across all patients and translates into clinical relevance by prolonging time to DIF, particularly in those with limited intracranial disease and those not receiving central nervous system-active agents.

Background: A previous Phase II clinical trial, conducted from 1995 to 2003, evaluated CNS germ cell tumors (GCTs) using a three-group treatment stratification based on histopathology. The primary objective of the study was to assess the long-term efficacy of standardized treatment regimens, while the secondary objective focused on identifying associated long-term complications.

Methods: A total of 228 patients were classified into 3 groups for treatment: germinoma (n = 161), intermediate prognosis (n = 38), and poor prognosis (n = 28), excluding one mature teratoma case. Treatment involved stratified chemotherapy regimens and varied radiation doses/coverage. Clinical data was retrospectively analyzed at a median follow-up of 18.5 years.

Results: The treatment outcomes for germinoma, with or without syncytiotrophoblastic giant cells, were similar. The 10- and 20-year event-free survival rates for the germinoma, intermediate, and poor prognosis groups were 82/76/49% and 73/66/49%, respectively. Overall survival (OS) rates were 97/87/61% at 10 years and 92/70/53% at 20 years. Germinomas in the basal ganglia, treated without whole-brain radiation therapy (WBRT), frequently relapsed but were effectively managed with subsequent WBRT. Deaths in germinoma cases had varied causes, whereas deaths in the poor prognosis group were predominantly disease-related. Nineteen treatment-related complications were identified in 16 patients, with cumulative event rates of 1.9% at 10 years and 11.3% at 20 years. OS rates at 1 and 2 years post-relapse for tumors initially classified as germinoma, intermediate, and poor prognosis were 94/88/18% and 91/50/9%, respectively.

Conclusions: Initial treatment intensity is crucial for managing non-germinomatous GCTs, while long-term follow-up for relapse and complications is imperative in germinomas. Irradiation extending beyond the immediate tumor site is essential for basal ganglia germinomas. Addressing relapse in non-germinomatous GCT remains a significant challenge.