Neuro-oncology最新文献

Background: Glioblastoma (GB) heterogeneity poses substantial challenges for diagnosis and treatment. IDH-wildtype GB may lack contrast enhancement on MRI and exhibit a "low-grade radiologic appearance" (non-CE GB), a phenomenon with unclear clinical implications. This study investigates the histopathological and molecular differences and survival outcomes between contrast-enhancing (CE) and non-CE GB.

Methods: This retrospective study at Heidelberg University Hospital analyzed 457 IDH-wildtype GB cases (09/2009-01/2021). Contrast enhancement on preoperative MRI was volumetrically assessed, classifying tumors as non-CE/CE GB using a 1 cm³ cut-off. Molecular and histopathological features, including microvascular proliferation, necrosis, and overall survival (OS), were compared between the groups.

Results: Of the initial cohort, 352 (77%) patients met the inclusion criteria, with 44 (12.5%) non-CE and 308 (87.5%) CE GB. The histopathological assessment revealed that non-CE GB was less likely to present traditional hallmarks of glioblastoma, such as microvascular proliferation (39% vs. 94%) and necrosis (25% vs. 92%) (p<0.001). In the non-CE group, 24 patients (55%) were diagnosed as molecular-GB, compared to only 8 patients (3%) in the CE group (p < 0.001). A significant difference was observed in Ki-67 levels, with non-CE GBs having a lower mean Ki-67 index of 18 ± 12% compared to 26 ± 13% in CE tumors (p<0.001). The median OS was 27.2 months (95%CI 19.8-NA) for non-CE and 14.7 months (95% CI, 13.2-17.1) for CE GB (p=0.0049).

Conclusions: IDH-wildtype GBs without contrast enhancement are often diagnosed based on molecular criteria due to less frequent histopathological hallmarks and are associated with prolonged OS.

Background: Glioblastoma (GBM) represents a complex ecosystem characterized by numerous interactions between tumor cells and the surrounding tumor microenvironment (TME). Here, we show that WNT10A, a member of the WNT family, plays an important role in GBM growth where its influence is mediated via both autocrine and paracrine pathways thereby stimulating not only the tumor cells but also normal cell types within the tumor microenvironment (TME).

Methods: In silico analysis was performed to identify high-expressing WNT family members in GBM. Knockdown and overexpression methods were used to examine the function of WNT10A in GBM cells and in orthotopic GBM xenografts in vivo. Co-immunoprecipitation (Co-IP) was used to confirm receptor binding and chromatin immunoprecipitation (ChIP) was performed to analyze transcriptional activation of downstream genes.

Results: WNT10A was found to be highly expressed in GBMs and its knockdown significantly suppressed GBM malignant behavior in vitro and in vivo. Co-IP assays confirmed an interaction between WNT10A and FZD1, which activated the JNK/c-Jun/FOSB signaling pathway and enhanced the transcription of FOSB. Importantly, GBM cells secreted WNT10A into the tumor microenvironment, leading to an activation of the PI3K-AKT pathway in tumor-associated macrophages (TAMs) and the JNK pathway in tumor-associated astrocytes. The latter caused a secretion of tumor-promoting cytokines IL-6, MCP-1, and angiogenin. LGK974, a PORCN inhibitor, inhibited the secretion of WNT10A to suppress the malignant GBM phenotype.

Conclusion: Our findings revealed that WNT10A is a critical factor promoting GBM progression through both autocrine and paracrine mechanisms. Thus, our findings provide the foundation for WNT-targeted clinical GBM treatment.

Background: Readmission following endoscopic endonasal transsphenoidal surgery (EETS) for pituitary neuroendocrine tumor (PitNET) and other sellar pathology is most commonly due to delayed hyponatremia. Studies suggest post-operative fluid restriction (FR) reduces delayed hyponatremia. We present a prospective randomized controlled study evaluating post-EETS FR.

Methods: 300 participants were scheduled for EETS (2016-2023) at a single institution. Patients with CKD, CHF, arginine vasopressin deficiency on post-operative day (POD) 3, chronic hyponatremia, and untreated adrenal insufficiency or hypothyroidism were excluded. Groups included control (ad-lib, n=94), moderate FR (1.8 L/day or 2 L/day weight >100 kg, n=39), and strict FR (1 L/day or 1.2 L/day weight >100 kg, n=62) from POD 3-14. Incidence of overall, moderate, and severe hyponatremia (Na <135, 125-129, and <125 mEq/L), readmission rates, fluid intake, and thirst were evaluated.

Results: The incidence of overall hyponatremia was 31.9%, 28.2%, and 21.0% in control, moderate FR, and strict FR groups, and the incidence of severe hyponatremia was 7.4%, 5.1%, and 0% in control, moderate FR, and strict FR groups. Nadir Na level was higher (1.81 mEq/L; 95% CI, 0.34 to 3.27; P=0.02) and severe hyponatremia occurred less frequently (95% CI, 0.00 to 1.02; P=0.04) in the strict FR vs. control group. Readmission was lower in the strict FR (1.6%, n=1) vs. control group (6.4%, n=6).

Conclusion: Post-operative FR decreases rates of delayed hyponatremia and related readmission compared to patients drinking ad-lib. Further studies are needed to assess the optimal volume and duration of FR after EETS.

Background: MAPK pathway inhibitors (MAPKi) have shown significant efficacy in treating childhood BRAF-activated brain tumors. For tumors harboring BRAFV600E mutations, the drugs are rarely curative, and patients can become refractory to treatment. MAPKi combining X-radiation therapy (XRT) may improve cure rate, but development of XRT-resistance is a challenge.

Methods: XRT-resistance was induced by multiple XRT cycles in pediatric BRAFV600E glioma patient-derived xenograft (PDX) models. RNA sequencing was performed to identify differentially expressed genes and pathways potentially contributing to XRT-resistance. Cells isolated from PDXs were used to test the contribution of specific genes and pathways to XRT-resistance. PDX models were used to evaluate the efficacy of targeted treatments combined with XRT.

Results: Tumors developed resistance after multiple cycles of XRT. MEK inhibition combining XRT significantly improved tumor control, compared to XRT alone, but resistance to combined therapy developed rapidly. RNA-sequencing analysis revealed up-regulation of MAPK and PI3K-mTOR signaling in the XRT-resistant tumors. Isolated cells showed in vitro resistance to XRT, which was partially reversed by inhibiting PI3K-mTOR. Up-regulation of TORC1 signaling in XRT naïve tumor cells, via constitutively active AKT or TSC2 deletion, conferred in vitro XRT-resistance.The pro-survival gene BIRC5 (Survivin), a target of TORC1 signaling, contributed to XRT-resistance. Combining trametinib-rapamycin with XRT significantly enhanced therapeutic efficacy in PDX models and prevented or delayed resistance development.

Conclusion: PI3K-mTOR activation promotes the development of XRT-resistance in pediatric BRAFV600E glioma. Dual targeting of MAPK and TORC1 signaling significantly enhances the therapeutic efficacy of XRT, and can potentially prevent the development of XRT-resistance. (250 words).

Background: Relapsed/refractory pediatric CNS tumors have a poor prognosis. EGFR is commonly overexpressed, but EGFRvIII mutations are uncommon. To target these tumors, we used chimeric antigen receptor (CAR) T cells with a binder based on mAb806 which recognizes ectopically expressed wild-type EGFR and EGFRvIII.

Methods: In this open-label phase 1 clinical trial, patients age 1-26 years with EGFR+ CNS tumors received weekly infusions of 1-2.5 x 107 CAR T cells into the tumor resection bed or the lateral ventricle via an implanted catheter. No lymphodepletion was used.

Results: Eleven patients were enrolled. Four (3 with high-grade glioma, 1 with atypical teratoid-rhabdoid tumor) were treated and received 5-10 CAR T cell infusions without dose-limiting toxicities. The trial closed prior to reaching planned dose regimens. All treatment-related adverse events were no higher than CTCAE grade 2. The most common were headache and nausea. One patient had a grade 1 seizure, and three had new sensory changes, weakness and/or urinary changes (grade 1-2) that were possibly related to CAR T cell infusion. Three of the four treated patients had progressive disease. One patient with spinal cord diffuse midline glioma had progressive peritumoral edema that could not be conclusively attributed to either progression or pseudoprogression and was therefore defined as stable disease, followed by a complete response to subsequent chemotherapy.

Conclusions: Intracranially infused EGFR806-CAR T cells were tolerable at tested doses, with a best response of stable disease. EGFR is a potentially useful target for cellular therapy against pediatric brain tumors, particularly high-grade gliomas.

Background: Factors that drive the development of diffuse midline gliomas (DMG) are unknown. Our study aimed to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in pediatric patients with DMG.

Methods: We assembled an international cohort of 252 pediatric patients with DMG, including diffuse intrinsic pontine glioma (n=153), with germline whole genome or whole exome sequencing.

Results: We identified P/LP germline variants in cancer predisposition genes in 7.5% (19/252) of patients. Tumor profiles differed, with absence of somatic drivers in the PI3K/mTOR pathway in patients with germline P/LP variants versus those without (P = 0.023). P/LP germline variants were recurrent in homologous recombination (n=9; BRCA1, BRCA2, PALB2) and Fanconi anemia genes (n=4). Somatic findings established that the germline variants definitively contributed to tumorigenesis in at least 1% of cases. One patient with recurrent DMG and pathogenic germline variants (BRCA2, FANCE) showed near-complete radiological response to PARP and immune checkpoint inhibition.

Conclusions: Our study determined the prevalence of pathogenic germline variants in pediatric DMG, and suggests a role in tumorigenesis for a subset of patients.

Background: The evolving treatment paradigm in children and adolescents with craniopharyngioma (CP) aims at minimizing late functional sequelae. Advanced radiotherapeutic techniques offer theoretical advantages of preserving neurological functions, however, clinical evidence of such is limited. The current study constitutes a secondary analysis of CP patients in a Randomized Control Trial testing Conventional RT (ConvRT) versus Stereotactic Conformal Radiotherapy (SCRT)(NCT00517959).

Methods: Eighty-two patients of CP (SCRT: 39, ConvRT: 43, Dose: 54Gy in 30 fractions) were analysed, assessing the clinical impact of dosimetric sparing on neurocognitive function, endocrine function, overall survival (OS) and local control (LC). Patients were longitudinally assessed from baseline through five years post-treatment using the WISC/WAIS scales.

Results: The median age was 13 years (IQR= 9-17 years). The 10-year OS and LC rates were 86.4% and 92.7%, respectively, with no significant difference between the arms.SCRT patients showed significant improvement in mean full-scale IQ (difference in slope=3.3 points per year, p= 0.01) and performance quotient (difference in slope=3.6, p= 0.04) compared to those treated with ConvRT. Freedom from cognitive decline (a 5-point drop) at 5 years was higher with SCRT (66.6% vs. 38.2%; HR=0.41, p=0.03). Younger age (<15 years) was a significant negative predictor of neurocognitive outcomes (p=0.002). SCRT patients also experienced lower cumulative incidence of new neuroendocrine dysfunction (25.7% vs. 48.8%, p=0.029).

Conclusion: SCRT offers excellent tumour control and similar survival with superior long-term preservation of neurocognitive and endocrine functions in CP patients compared to conventional RT. High precision RT should constitute the standard of care in CP.

Background: Glutamine is an important nutrient for cancer cell growth that provides biological sources for nucleic acid and fatty acid synthesis, but the role of glutaminolysis in signal transduction and glioblastoma (GBM) progression remains little known.

Methods: Knockdown and overexpression cells were obtained to explore the functional roles of glutamate dehydrogenase 1 (GDH1) in cell proliferation, tumor formation, and aerobic glycolysis. RNA-seq, Chromatin immunoprecipitation, luciferase assay, and western blot were performed to verify the regulation of the EGFR-AKT pathway by the GDH1 (also known as GLUD1) and KDM6A. Metabolite-level measurements and Seahorse Assay were performed to assess the functional role of GHD1 in reprogramming glycolysis.

Results: Here, we report that GDH1 catalytic glutaminolysis is essential for GBM cell line proliferation and brain tumorigenesis even in high-glucose conditions. Glutamine is metabolized through glutaminolysis to produce α-ketoglutarate (α-KG). We demonstrate that glutamine in combination with leucine activates mammalian TORC1 by enhancing glutaminolysis and α-KG production. α-KG increases the transcription of PDPK1 by reducing the suppressive histone modification H3K27me3 and then promotes the activation of the PI3K/AKT/mTOR pathway. This transcriptional activation induced by α-KG requires histone demethylase KDM6A, which is a 2-oxoglutarate oxygenase that plays an important role in converting α-KG to succinate. Furthermore, we show that GDH1-catalytic glutaminolysis also increases the expression of HK2 and promotes glycolysis in high-glucose conditions dependent on KDM6A-mediated demethylation of H3K27.

Conclusions: These findings suggest a novel function of glutaminolysis in the regulation of signal transduction and metabolism reprogramming and provide further evidence for the unique role of glutaminolysis in GBM progression.