Neuro-oncology advances最新文献

Background: Benefits of tumor resection in elderly glioblastoma multiforme (GBM) patients within the framework of multimodal treatment remains a matter of debate. This retrospective, multicenter analysis aims at the identification of patients who are most likely to benefit from microsurgical resection, and the development of a scoring system to improve future decision-making.

Methods: Demographic and outcome data of GBM patients aged 65 years and older, who underwent resection or biopsy at three centers between 2003 and 2022, were analyzed. Frailty was assessed by the Modified 5-Item Frailty Index (mFI-5).

Results: We studied 537 patients (median age 73.4 years); 369 (68.7%) underwent resection and 168 (31.3%) underwent biopsy. Resected patients were younger, were preoperatively more commonly functionally independent, were less frail, and had larger tumor volumes (all P < .001). The median overall survival was 9.1 [confidence interval (CI) 95% 7.9-10.5] months for resected and 2.8 (CI 95% 2.1-4.3) months for biopsied patients (P < .001). The strongest preoperatively determinable predictors for poor survival were older age, significant frailty (mFI-5 ≥ 2), and deep-seated tumor location for, both, resected and biopsied patients (P < .001). Based on this, a score (0-5 points) incorporating these parameters was developed. Among patients with assumed favorable prognosis (score ≤ 1) the median survival difference between resection and biopsy was 7.5 months, whereas in case of poor prognosis (score ≥ 4) the difference was 2.1 months. No long-term survivors ≥24 months had a score of ≥3 points.

Conclusions: Selected elderly glioblastoma patients might benefit from microsurgical resection. A score to guide neurosurgical treatment decision-making and patient counseling was developed.

Background: Glioblastoma (GBM) and cells of the tumour microenvironment (TME) secrete extracellular vesicles (EVs) into the plasma that contain genetic and protein cargo, which function in paracrine signaling. Isolation of these EVs and their cargo from plasma could lead to a simplistic tool that can inform on diagnosis and disease course of GBM.

Methods: In the present study, plasma EVs were captured utilizing a peptide affinity method (Vn96 peptide) from GBM patients and normal controls followed by next generation sequencing to define a small RNA (sRNA) signature unique to GBM.

Results: Over 750 differentially expressed sRNA (miRNA, snoRNA, lncRNA, tRNA, mRNA fragments and non-annotated regions) were identified between GBM and controls. MiEAA 2.0 pathway analysis of the miRNA in the sRNA signature revealed miRNA highly enriched in both EV and GBM pathways demonstrating the validity of results in capturing a signal from the TME. Also revealed were several novel GBM plasma EV sRNA biomarkers including lncRNA RPPH1 (Ribonuclease P Component H1), RNY4 (Ro60-Associated Y4) and RNY5 (Ro60-Associated Y5). Furthermore, in paired longitudinal patient plasma sampling, RPPH1 informed on surgical resection (decreased on resection) and importantly, RPPH1 increased again on clinically defined progression.

Conclusions: The present provides preliminary data that support the continued investigation of plasma EV sRNA sampling (and particularly RPPH1) as part of a multi-pronged approach to GBM diagnosis and disease course surveillance.

Background: The gold standard for the diagnosis of brain tumors comprises neurosurgical biopsies or resections for tissue acquisition. Depending on the anatomical location of the tumor, this might not always be feasible. The aim of this study was to assess whether targeted sequencing of cell-free DNA (cfDNA) could be applied in a clinical setting for the detection of cancer-specific mutations in cerebrospinal fluid (CSF) and blood using a widely available panel, investigating if this approach would facilitate brain tumor diagnosis.

Methods: Patients with newly suspected or confirmed CNS tumors or suspected leptomeningeal metastasis were included. CSF and blood were sampled for each patient. Using next-generation sequencing (NGS), targeted sequencing was performed on cfDNA. If available, matched tissue samples were also sequenced using the same gene panel.

Results: We investigated 58 samples from 29 patients. Sequencing was successful in 16 CSF samples (55%) and 29 blood samples (100%). On average, more tumor-specific mutations were found in CSF compared to blood. Patients in whom cfDNA sequencing in CSF was successful had tumors with a significantly shorter distance to the CSF space and were larger in size. In 2 cases, where surgeries were not considered because of high surgical risk due to the anatomical locations of the lesions, the diagnosis was aided by CSF sequencing results. One primary CNS lymphoma and 1 H3 K27M diffuse midline glioma were identified, respectively.

Conclusions: NGS-based targeted sequencing in CSF has the potential to facilitate brain tumor diagnosis in patients presenting with new cerebral lesions.

Background: The efficacy of ipilimumab and nivolumab (ipi/nivo) for melanoma brain metastases (MBMs) has been previously reported, leading to uncertainty regarding the optimal role of comprehensive stereotactic radiosurgery (cSRS). We therefore conducted a single-institution retrospective study to compare outcomes of upfront versus deferred cSRS for MBM treated with ipi/nivo.

Methods: We identified patients who started ipi/nivo for newly diagnosed MBMs between 2018 and 2023, with or without upfront cSRS. Patients with >15 MBMs, leptomeningeal disease, or whole-brain radiotherapy at baseline were excluded. Outcomes were compared using multivariable regression and reported as adjusted hazard ratios (aHRs) with 95% CIs.

Results: Of the 132 patients identified, 52.3% received upfront cSRS and 47.7% did not. Patients who received upfront cSRS had larger maximum MBMs (median 2.3 vs 0.7 cm; P < .001), more symptomatic MBMs (59.4% vs 11.1%; P < .001), higher rates of upfront craniotomy (47.8% vs 7.9%; P < .001), and fewer BRAF V600 mutations (34.8% vs 54.0%; P = .035). Upfront cSRS was not associated with longer overall survival (median 47.0 mo vs not reached; aHR = 1.01 [95% CI, 0.60-1.68]; P = .98) but was associated with reduced incidence of intracranial progression (median 37.6 vs 5.5 mo; aHR = 0.40 [95% CI, 0.25-0.64]; P < .001).

Conclusions: In this retrospective study, upfront cSRS was more often used in patients with higher-risk MBM and was associated with improved intracranial control, although no significant survival benefit was observed. These findings suggest that starting ipi/nivo alone may be reasonable for lower-risk MBM, but prospective studies are needed to guide optimal integration of cSRS.

Background: Spinal chondrosarcomas are rare, aggressive bone tumors with limited data on optimal radiotherapy strategies, particularly regarding the comparison between proton and photon therapies. This study aims to evaluate long-term survival outcomes and identify effective treatments and risk factors using the National Cancer Database.

Methods: Patients diagnosed with spinal chondrosarcomas were categorized into radiation and no-radiation groups. The radiation group was subdivided into proton and photon therapy cohorts. Univariate and Kaplan-Meier analyses assessed demographic, clinical, and survival outcomes. Multivariate Cox proportional hazards models identified prognostic factors, and survival predictive models were evaluated using Area Under the Curve (AUC) metrics.

Results: Of 1971 patients, 343 (17.4%) received radiation. Surgery was less common in the radiation group (53.9% vs 82.6%, P < .001). Combined surgery and radiation had the best survival outcomes, with proton therapy showing superior survival to photons (P < .001). High-dose radiation (Biologically Effective Dose [BED] >70 Gy) and Stereotactic Body Radiation Therapy (SBRT) improved survival (P < .001). Surgery was associated with increased mortality risk (hazard ratio [HR] = 0.35, P < .001), while radiation showed increased risk (HR = 1.31, P = .003). Machine learning identified tumor size thresholds of 75 mm for photon and 70 mm for proton therapy as predictive of mortality. DeepSurv (AUC = 0.708) identified distant metastasis, tumor size, and age as important prognostic factors for 10-year survival.

Conclusion: Gross total resection (GTR) is the most effective treatment for spinal chondrosarcoma. High-dose radiation therapy (BED > 70 Gy) can be combined with surgery to improve survival in advanced cases. Proton therapy offers superior long-term survival compared to photons, and dose-escalated techniques (Stereotactic Radiosurgery [SRS] and Intensity-modulated radiation therapy [IMRT]) show potential in enhancing outcomes.

Background: Murine double minute 2 (MDM2) inhibitors reactivate wild-type p53 and are a promising therapy for glioblastoma, IDH-wildtype (GBM). Brigimadlin is a highly potent MDM2 inhibitor being tested in a phase 0/1 clinical trial in combination with radiation in GBM.

Methods: Brigimadlin pharmacokinetics, pharmacodynamics, and efficacy were evaluated in GBM patient-derived xenografts (PDXs).

Results: In vitro, brigimadlin impaired viability in TP53 wild-type GBM with an IC₅₀ of 0.8-6.6 nmol/L, but sensitivity did not correlate with MDM2 amplification. In vivo, MDM2 amplification was highly correlated with efficacy. In subcutaneous PDXs, 1 or 2 mg/kg brigimadlin dosed weekly was highly effective in 2 MDM2-amplified PDXs. At 2 mg/kg, brigimadlin delayed tumor regrowth by >5-fold in the MDM2-amplified PDXs compared to 1.5-fold in a non-amplified PDX. In orthotopic PDXs, efficacy was more limited, but 2 mg/kg brigimadlin enhanced the response to fractionated radiation in MDM2-amplified PDXs. Consistent with blood-brain barrier efflux limiting drug distribution, 2 mg/kg brigimadlin extended survival by >5-fold in an MDM2-amplified orthotopic PDX established in Rag1^-/-Abcb1a^-/- Abcg2^-/- mice. In pharmacodynamic studies, p53 target genes were upregulated at both subtherapeutic and therapeutic dose levels, and the extent of activation did not correlate with MDM2 status. Concentrations of brigimadlin in tumor tissue were approximately 10-fold higher in MDM2-amplified tumors, and intracellular drug levels directly correlated with drug-dependent MDM2 upregulation, suggesting target binding affects drug accumulation.

Conclusions: Brigimadlin is highly effective in MDM2-amplified GBM when adequate drug levels are achieved in tumor tissue. MDM2 amplification impacts both treatment efficacy and intratumoral drug accumulation.

Background: Non-germinomatous germ cell tumors (NGGCTs) occur 3.5 times more frequently in Chinese children than in western populations. This study aimed to evaluate treatment outcomes, prognostic factors, and diagnostic challenges in a Chinese cooperative group, with particular focus on the roles of pathology and surgical intervention.

Methods: We retrospectively analyzed 62 consecutively diagnosed pediatric patients with NGGCT (September 2018-June 2023) from Shanghai Children's Medical Center and Huashan Hospital. NGGCT was diagnosed by histopathology with/without elevated tumor markers (n = 46) or by elevated markers alone (n = 16). All patients received standardized treatment according to Children's Oncology Group ACNS0122 protocol. Whole-exome sequencing was performed on 12 paired tumor-blood samples to characterize molecular alterations.

Results: The study cohort included 49 males and 13 females (median age, 9.8 year). Primary locations were mainly pineal (58%) and suprasellar (29%). Treatment delays (>6 mo) occurred in 21% of patients, particularly those with non-pineal locations and endocrine symptoms. The 3 years event-free survival and overall survival rates were 81.9 ± 5.4% and 91.3 ± 3.7%, respectively. Univariate analysis identified poor prognostic factors: elevated AFP >200 ng/mL, spinal metastases, and lack of complete/partial response after induction chemotherapy. Surgical resection of small residual tumors (<2 cm) provided no survival benefit. Molecular analysis revealed KRAS and KIT as the most frequent mutations, with chromosome 12p abnormalities in 50% of cases.

Conclusions: Standardized multidisciplinary treatment achieves favorable outcomes comparable to international benchmarks. Aggressive surgery does not improve survival when tumor markers normalize. Diagnostic delays remain common, emphasizing the need for improved awareness and referral systems in China.

Glioblastoma (GBM) is the most aggressive primary brain tumor, characterized by rapid progression, extensive inter- and intra-tumoral heterogeneity, and resistance to standard-of-care, including radiotherapy. Radiotherapy remains a cornerstone of GBM management, but its efficacy is limited by complex tumor biology and mechanisms of radioresistance. This review explores the advances in radiotherapy for GBM, focusing on the interplay between tumor biology and emerging treatment strategies. Hallmarks of GBM biology, including hypoxia, the robust DNA repair mechanisms, the immunosuppressive tumor microenvironment (TME), and the extensive plasticity contribute to therapeutic resistance. Innovative approaches in radiotherapy may allow to address these challenges. Charged particle therapies (CPTs), including proton and carbon ion therapy, offer superior precision and enhanced biological effectiveness by delivering lethal doses to tumor cells while sparing surrounding healthy tissue. FLASH therapy, using ultra-high dose rates, could reduce normal tissue toxicity without compromising tumor control. Furthermore, targeted radionuclide therapy harnesses tumor-specific targets to systemically deliver radiopharmaceuticals carrying therapeutic radionuclides directly to cancer cells, improving specificity and reducing off-target effects. This review highlights the promise of these novel radiotherapy modalities to address GBM's inherent heterogeneity and treatment resistance. By integrating advancements in technology with novel insights into GBM biology, these approaches may significantly improve patient outcomes.

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.