Journal of Neuro-Oncology最新文献

Purpose: Hippocampal injury from WBRT contributes to neurocognitive decline in brain malignancy patients. HA-WBRT may mitigate this by reducing hippocampal radiation exposure, but its feasibility in PCNSL remains unassessed regarding hippocampal involvement and failure rates. This study evaluates hippocampal involvement at diagnosis and after treatment in PCNSL patients.

Materials and methods: We conducted a retrospective analysis of 278 immunocompetent PCNSL patients diagnosed between 2000 and 2021. Following high-dose methotrexate-based induction chemotherapy, patients either received consolidation therapy, including RT, cytarabine alone, or autologous stem cell transplantation or underwent observation. Hippocampus was outlined on T1 MRI images and expanded by a 5 mm margin to create the hippocampal avoidance region (HAR). Hippocampal failure was defined as recurrence or progression at HAR. The median follow-up was 38.7 months (range 3.1-239.4 months).

Results: Of the 278 patients diagnosed with PCNSL, 39.9% presented initial lesions at HAR. After induction therapy, 212 evaluable patients received consolidation treatments or observation. Intracranial failures occurred in 47.6% (n = 101), with 66.3% (n = 67) occurring outside the HAR and 33.7% (n = 34) inside the HAR. Unifocal disease (HR 0.61, 95% CI 0.39-0.96, p = 0.025) was associated with a lower risk of hippocampal failures, while initial HAR involvement significantly increased the risk (HR 2.26, 95% CI 1.18-4.47, p = 0.018). Patients with unifocal disease outside the HAR had the lowest 3-year hippocampal failure rate (6.2%). RT that included the hippocampus did not significantly affect hippocampal failure rates in patients without initial HAR lesions (p = 0.282), with three-year rates of 9.2 vs. 14.6% for other treatments. However, among patients with initial HAR involvement, RT including the hippocampus significantly reduced hippocampal failure rates compared to other approaches (p = 0.002). Hippocampal failure rates were comparable, with conventional WBRT at 14.6% and HA-WBRT at 19% in patients without initial HAR lesions (p = 0.734).

Conclusion: The routine application of the HA-WBRT strategy is not supported due to the high risk of hippocampal failures in general and requires further investigation to establish its feasibility and safety in well-defined subgroups. Our results suggest that the HA-WBRT strategy could be evaluated for select PCNSL patients with unifocal lesions or those located outside the HAR.

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: The goal of this study was to investigate the role and therapeutic targeting of T-type calcium channels in medulloblastoma, a common and deadly pediatric brain tumor that arises in the cerebellum.

Methods: T-type calcium channel expression was assessed in publicly available bulk and single cell RNA-seq datasets. The effects of T-type calcium channel blocker mibefradil on cell growth, death and invasion were assessed with cell counting, alamar blue, trypan blue and transwell assays. Proteomic-based drug target and signaling pathway mapping was performed with Reverse Phase Protein Arrays (RPPA). Co-expression modules of single cell RNA-seq data were generated using high dimensional weighted gene co-expression network analysis (hdWGCNA). Orthotopic xenografts were used for therapeutic studies with the T-Type calcium channel blocker mibefradil.

Results: T-type calcium channels were upregulated in more than 30% of medulloblastoma tumors and patients with high expression associated with a worse prognosis. T-type calcium channels had variable expression across all the subgroups of medulloblastoma at the bulk RNA-seq and single-cell RNA-seq level. Mibefradil treatment or siRNA mediated silencing of T-type calcium channels inhibited tumor cell growth, viability and invasion. RPPA-based protein/phosphoprotein signal pathway activation mapping of T-type calcium channel inhibition and single cell hdWGCNA identified altered cancer signaling pathways. Oral administration of mibefradil inhibited medulloblastoma xenograft growth and prolonged animal survival.

Conclusion: Our results represent a first comprehensive multi-omic characterization of T-type calcium channels in medulloblastoma and provide preclinical data for repurposing mibefradil as a treatment strategy for these relatively common pediatric brain tumors.

Purpose: Systemic therapies are increasingly being considered as primary treatments for brain metastases (BM), deferring the upfront use of local treatment modalities. However, evidence to support this paradigm shift is difficult to interpret given the volume of data published and the intricacies of the outcomes reported. The objective of this narrative review is to evaluate the current evidence guiding treatment selection for BM patients by assembling and analyzing a detailed dataset of clinical trials, completed and published during the last two decades.

Methods: Obstacles in interpreting the results of prospective systemic therapy clinical trials are detailed, including non-standardized study cohorts, inconsistent use of response assessment criteria, insufficient endpoint definition for central nervous system (CNS) efficacy, and under-reporting of previous radiotherapy. The paucity of prospective data to guide radiation therapy options is also addressed, and caveats of the available published evidence are detailed.

Results: Proposed treatment and follow-up recommendations for patient with newly diagnosed BM are provided based on currently available evidence.

Conclusion: Prospective trials evaluating contemporary treatment paradigms and defining the respective roles of systemic and local therapies are eagerly awaited.

Purpose: Glioblastoma (GBM) exhibits a high ROS character, giving rise to an immunosuppressive microenvironment and tumor vascular abnormality. This study investigated the potential effect of N-acetylcysteine (NAC), an antioxidant, on primary and recurrent mouse brain tumors.

Methods: We measured reactive oxygen species (ROS)/ glutathione (GSH) levels in human GBM. Additionally, we conducted NAC trials on primary mouse brain tumor models (GL261-Luc, CT2A-Luc) and a recurrent mouse GBM model (GL261-iCasp9-Luc). After brain tumor inoculation, mice received a daily 100 mg/kg NAC treatment, and the tumor volume was monitored via IVIS imaging. The efficacy of NAC was evaluated through survival time, tumor volume, ROS/GSH levels, M1/M2 macrophages, immune cells infiltration, and tumor vascularization.

Results: Human GBM suffered from significant oxidative stress. With NAC treatment, mouse brain tumors exhibited a lower ROS level, more M1-like tumor-associated macrophages/microglia (TAMs), more CD8 + T cell infiltration, and a normalized vascular character. NAC inhibited tumor growth and suppressed recurrence in mouse brain tumor models.

Conclusion: NAC is a promising adjunctive drug to remodel the brain tumors microenvironment.

Introduction: Craniopharyngioma is a rare solid-cystic tumor of the hypothalamopituitary region. Two distinct craniopharyngioma types (formerly subtypes), adamantinomatous and papillary, have been described. These tumors often manifest with neuroendocrine dysfunction, vision problems, hydrocephalus, and cognitive changes. Despite efforts to spare vital brain structures, conventional treatments such as surgery and radiation can exacerbate preceding deficits and contribute to permanent neurologic impairment. Recent studies have identified BRAF-V600E mutations in nearly all papillary craniopharyngiomas (PCP), and CTNNB1/Wnt pathway alterations in adamantinomatous craniopharyngiomas (ACP). These discoveries have advanced our understanding of craniopharyngioma pathogenesis and have opened opportunities for targeted biological treatments.

Purpose: The primary objective of this article is to review the current landscape of targeted treatments in papillary and adamantinomatous craniopharyngioma.

Results: Treatment of PCP with BRAF/MEK inhibition has demonstrated durable tumor response in the adjuvant and neoadjuvant settings in multiple case studies and one phase II clinical trial. Although treatment advances are more limited for ACP, CTNNB1/Wnt pathway inhibitors showed promising results in pre-clinical studies and are under continued investigation.

Conclusion: The efficacy of BRAF/MEK inhibition in PCP supports the use of targeted therapy in patients with newly diagnosed PCP. The optimal targeted treatment combinations and their timing, duration, long-term effects, and sequencing with traditional therapeutic modalities have not been established and warrant further study. Targeted therapies represent a significant advancement in the field of oncology, and craniopharyngiomas are viable candidates for these approaches pending further research.

Introduction and objectives: Leptomeningeal disease (LMD) involves disseminating cancer cells to the leptomeninges and cerebrospinal fluid. The impact of intracranial parenchymal brain metastases and extracranial disease burden at LMD diagnosis remains unclear. This study evaluates these factors alongside local and systemic therapies before and after LMD diagnosis.

Methods: A retrospective analysis was conducted on 188 patients diagnosed with LMD between 2011 and 2024. Data on demographics, imaging findings, and treatments were collected. Kaplan-Meier estimates were used for survival analysis, and independent prognostic factors were identified using a backward-stepwise Cox regression model.

Results: Primary cancers included breast cancer (34.0%), non-small cell lung cancer (22.3%), and melanoma (14.4%). LMD was diagnosed via MRI in 56.4% of cases, cerebrospinal fluid (CSF) cytology in 2.7%, and both in 41.0%. Median overall survival was 2.8 months [95% CI: 2.4 - 3.7]. Independent prognostic factors for improved survival included male sex (HR: 0.61 [95% CI: 0.40 - 0.93], p = 0.020), absence of hydrocephalus at LMD diagnosis (HR: 0.42 [95% CI: 0.22 - 0.79], p = 0.007), and targeted therapy post-diagnosis (HR: 0.33 [95% CI: 0.20 - 0.55], p < 0.001). Two or more lines of systemic therapy before LMD diagnosis increased mortality risk (HR: 1.73 [95% CI: 1.16 - 2.59], p = 0.007). Lack of CNS parenchymal disease at LMD diagnosis also increased risk (HR: 0.51 [95% CI: 0.30 - 0.89], p = 0.017). Pre-diagnosis radiation therapy showed no survival benefit, while post-diagnosis radiation improved outcomes (HR: 0.47 [95% CI: 0.32 - 0.70], p < 0.001).

Conclusion: Absence of hydrocephalus and use of targeted therapy post-diagnosis are favorable prognostic factors, while extensive prior systemic therapy and CNS parenchymal disease worsen outcomes. Tailored therapies addressing intracranial disease are crucial for improving survival in LMD patients.

Purpose: Patients with metastatic melanoma frequently develop brain metastases. Due to recent advances in melanoma therapy, we evaluated the timing of brain metastases diagnosis in relation to outcome during melanoma immunotherapy.

Methods: Patients who received 1st -line treatment with ipilimumab plus nivolumab for metastatic melanoma were identified via a database search. Patient characteristics and outcomes were recorded.

Results: Of 73 patients that met study criteria, 20 patients developed brain metastases (27.4%). Of these 20 patients, 14 had brain metastases at diagnosis of metastatic disease, Only 6 progressed in the brain following immunotherapy. All but one patient with brain metastases at diagnosis were symptomatic. Following immunotherapy, 4/15 (all with BRAF V600E mutations) achieved complete remissions and prolonged survival. Each of these patients was able to undergo elective treatment discontinuation. One additional patient developed stable disease. Delayed brain metastases proved to be infrequent (6/59 patients). Delayed brain metastases were always diagnosed within the first 15 months of treatment. Five of these 6 patients died, with a median progression-free survival of only 2.1 months.

Conclusion: Brain metastases frequently complicated the course of metastatic melanoma. Patients with symptomatic brain metastases at diagnosis had a potential for durable remissions following multidisciplinary treatment, particularly if a BRAF V600E mutation was present. This included 2 of 10 patients who were on steroid treatment prior to the start of immunotherapy. Treatment with combination immunotherapy seemed to reduce the development of subsequent brain metastases. Patients who developed delayed brain metastases had a very poor outlook, despite attempted salvage therapy.

Purpose: This study analyzed spinal subependymoma (SP-SE) cases to evaluate treatment outcomes and identify factors influencing patient outcomes.

Method: Clinical data from our institution, along with relevant literature, were reviewed and summarized. Univariate and multivariate logistic regression analyses were conducted to assess factors impacting the prognosis of patients with primary spinal ependymomas.

Results: Our cohort included 16 males and 11 females, with a mean age of 46.2 ± 12.1 years. Tumors most commonly involved the thoracic spinal cord (37.0%) and an average of 4.8 segments. Approximately half of the tumors exhibited intramedullary to extramedullary growth (48.1%), and the tumors were predominantly eccentric in growth (85.2%). The median symptom duration was 48.0 months (IQR: 18.0-78.0 months), with limb weakness as the most frequent symptom. The median follow-up period was 61.0 months (IQR: 26.0-96.0 months). At the final follow-up, tumor regrowth occurred in 1 patient (3.7%), and 9 patients (33.3%) achieved good neurological outcomes (modified McCormick Scale [MSS] grades I). Multivariate logistic regression analysis revealed that tumors located at the T3-9 vertebral level were associated with worse postoperative neurological function (OR: 0.070, 95% Confidence Interval [CI]: 0.006-0.826, P = 0.035). Additionally, although the difference was not statistically significant, male gender also showed a trend towards an association with worse postoperative neurological function (OR: 0.126, 95% CI: 0.014-1.119, P = 0.063).

Conclusion: SP-SE generally follows a benign clinical course with favorable long-term survival. However, tumors located at T3-T9 and male patients tend to have worse postoperative neurological outcomes, requiring special attention during treatment.