Neuro-oncology advances最新文献

Background: Glioblastoma (GBM) is a dreadful brain tumor, with a particular relationship to the adult subventricular zone (SVZ) that has been described as relevant to disease initiation, progression, and recurrence.

Methods: We propose a novel strategy for the detection and tracking of xenografted GBM cells that are located in the SVZ, based on an intracerebroventricular (icv) recombinant adeno-associated virus (AAV)-mediated color conversion method. We used different patient-derived GBM stem-like cells (GSCs), which we transduced first with a retroviral vector (LRLG) that included a lox-dsRed-STOP-lox cassette, upstream of the eGFP gene, then with rAAVs expressing the Cre-recombinase. Red and green fluorescence is analyzed in vitro and in vivo using flow cytometry and fluorescence microscopy.

Results: After comparing the efficiency of diverse rAAV serotypes, we confirmed that the in vitro transduction of GSC-LRLG with rAAV-Cre induced a switch from red to green fluorescence. In parallel, we verified that rAAV transduction was confined to the walls of the lateral ventricles. We, therefore, applied this conversion approach in 2 patient-derived orthotopic GSC xenograft models and showed that the icv injection of an rAAV-DJ-Cre after GSC-LRLG tumor implantation triggered the conversion of red GSCs to green, in the periventricular region. Green GSCs were also found at distant places, including the migratory tract and the tumor core.

Conclusions: This study not only sheds light on the putative outcome of SVZ-nested GBM cells but also shows that icv injection of rAAV vectors allows to transduce and potentially modulate gene expression in hard-to-reach GBM cells of the periventricular area.

Atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive brain tumors primarily observed in infants. The only characteristic, recurrent genetic aberration of AT/RTs is biallelic inactivation of SMARCB1 (or SMARCA4). These genes are members of the mSWI/SNF chromatin-remodeling complex, which regulates various developmental processes, including neural differentiation. This review explores AT/RT subgroups regarding their distinct SMARCB1 loss-of-function mechanisms, molecular features, and patient characteristics. Additionally, it addresses the ongoing debate about the oncogenic relevance of cell-of-origin, examining the influence of developmental stage and lineage commitment of the seeding cell on tumor malignancy and other characteristics. Epigenetic dysregulation, particularly through the regulation of histone modifications and DNA hypermethylation, has been shown to play an integral role in AT/RTs' malignancy and differentiation blockage, maintaining cells in a poorly differentiated state via the insufficient activation of differentiation-related genes. Here, the differentiation blockage and its contribution to malignancy are also explored in a cellular context. Understanding these mechanisms and AT/RT heterogeneity is crucial for therapeutic improvements against AT/RTs.

Background: Primary optic nerve sheath meningiomas (ONSMs) represent a group of benign tumors originating from the optic nerve sheath, typically causing painless, gradual onset monocular visual loss, which can result in blindness if left untreated. Radiation therapy represents an important treatment option for patients with ONSM, allowing for preservation and potential improvement in visual function. In particular, proton radiotherapy may enable a reduction of the side effects due to its physical advantage of an inverted dose profile with a steep dose gradient. The study investigates the visual acuity, local tumor control, and treatment-related toxicities following proton beam radiotherapy with a single institutional cohort comprising 32 patients treated for ONSM.

Methods: Patients with primary ONSM, either histologically (16/32) or radiologically confirmed (16/32), which were treated at the Department of Radiation Oncology at the University Hospital Heidelberg (Germany) were assessed in regard to their visual outcomes, treatment toxicity, and local tumor control following radiotherapy according to response assessment in neuro-oncology criteria.

Results: After a median follow-up time of 39.5 months, the 5-year local progression-free survival was estimated at 100%, with 84.4% of patients reporting improvement or stability in visual acuity during their last follow-up. Radiation-induced optic neuropathy (RION) was encountered in 9.4%.

Conclusions: Our study demonstrates proton beam therapy as a safe and effective treatment alternative in the therapeutic management of ONSMs. RION represents a rare but dreaded complication after treatment. Future head-to-head comparisons with photon radiotherapy in a prospective setting are required to demonstrate a potential, additional clinical benefit.

Background: Atypical and anaplastic meningiomas account for 20% of all meningioma cases. Solitary fibrous tumor (SFT) is a type of soft tissue sarcoma with similar attributes to meningioma. For patients with refractory or recurrent disease after previous surgery or radiotherapy, there is no effective treatment. Pembrolizumab, an anti-programmed cell death 1 (PD-1) antibody, is an effective treatment for various solid tumors. PD-1 ligand is highly expressed in aggressive meningiomas. We aimed to assess the effectiveness of pembrolizumab in treating meningioma and SFT recurrence after surgery and radiation therapy.

Methods: This prospective single-arm phase II trial comprised 15 patients with recurrent meningioma and 3 with anaplastic SFT, treated at a single institution during 2018 to 2022. The study was terminated due to a lack of efficacy and slow accrual. The primary endpoint was 6-month progression-free survival (PFS-6).

Results: Median progression-free survival (PFS) was 2.6 months, and median overall survival (OS) was 40 months. The 6- and 12-month PFS were both 11.1%. The 6- and 12-month OS were 94.4% and 61.1%, respectively. According to the Response Assessment in Neuro-Oncology (RANO) criteria, the overall response rate was 11%, with 2 patients achieving stable disease and 2 with partial response. Three patients (16.7%) developed grade 3 toxicity.

Conclusions: Our results showed that pembrolizumab failed to improve PFS-6 in patients with aggressive meningioma or anaplastic SFT. However, two patients, one with atypical meningioma and one with anaplastic SFT, achieved a partial response. More clinical studies are needed to identify which subset of patients may benefit from this treatment.

Patients with rhabdoid tumor predisposition syndrome (RTPS) harbor germline alterations in the epigenetic regulator genes SMARCB1 or SMARCA4. Patients usually present with atypical teratoid/rhabdoid tumor (AT/RT) of the brain or malignant rhabdoid tumor (MRT) arising outside the central nervous system. Intensive treatment can lead to remissions, however tumors frequently recur or synchronous or metachronous tumors appear. A maintenance or secondary prevention regimen may prevent these aggressive tumors. Potential maintenance regimens may include low-dose traditional chemotherapy or different epigenetic therapies designed to target the epigenetic imbalance that drives RTs. We here review several potential maintenance regimens that may be useful in RTPS.

Background: GammaTile (GT), a form of brachytherapy utilizing cesium-131 seeds in a bioresorbable collagen tile, has gained popularity for the treatment of recurrent intracranial tumors and more recently for newly diagnosed metastases. This study reports early experience utilizing GT in upfront brain metastases with a focus on clinical applications and perioperative safety.

Methods: The STaRT Registry (NCT04427384) was queried for all patients receiving GT for upfront metastases from August 2021 to August 2023. Data regarding patient demographics, procedure details, and adverse events (AEs) were extracted and analyzed.

Results: Twenty-eight patients, median age 65 years (range 28-81), with 30 treated metastases were reported from 6 institutions. Patients had 2.8 metastases on average (range 1-15) at the time of surgery; however, most patients had a single metastasis (60.7%). The mean diameter of treated metastases was 3.4 cm (range 1.5-4.7). A median of 4.0 tiles (range 1-10) were used per tumor. The median follow-up was 3.0 months (range 1.0-11.2) with 6 attributed AEs (21.4%), including 1 grade ≥ 3 (infection). In the immediate postoperative period (<14 days), 2 patients reported pain or headache, and 1 reported facial edema. One patient developed seizures on postoperative day 8 requiring medication. At 1-month follow-up, there was 1 superficial wound infection, in a previously colonized patient, requiring surgical intervention without explantation of tiles. At 3-month follow-up, 1 patient reported facial pain not requiring treatment. There were no symptomatic hematomas.

Conclusions: GT demonstrates a favorable safety profile in upfront brain metastases with a 3.6% rate of serious AEs (grade ≥ 3) within 90 days of the procedure.

Background: Our aim is to investigate the association of treatment with survival in patients with diffuse intrinsic pontine glioma (DIPG) by examining 6 historical treatment paths.

Methods: We retrospectively analyzed data from 409 patients with radiologically centrally reviewed DIPG, sourced from the German Society of Pediatric Oncology and Hematology HIT-HGG trial database and the SIOPE-DIPG/DMG Registry. Survival outcomes were estimated using the Kaplan-Meier method, and univariable and multivariable Cox proportional hazard models were estimated to study treatment effects.

Results: The median overall survival (OS) from diagnosis was 11.2 months (95% confidence interval [CI], 10.5-11.9). Patients who by choice received no frontline treatment had an OS of 3.0 months (95% CI, 2.0-4.0), while those treated with radiation therapy (RT) alone had a median OS of 10.4 months (95% CI, 9.1-11.8). Those receiving RT combined with chemotherapy had the longest median OS of 11.7 months (95% CI, 10.8-12.6). The median post-progression survival (PPS) was 4.1 months (95% CI, 3.5-4.7). Patients who relapsed and did not receive treatment had a PPS of 2.2 months (95% CI, 1.8-2.6), while those treated with chemotherapy alone had a PPS of 4.4 months (95% CI, 3.7-5.0), and those who underwent reirradiation, with or without chemotherapy, had the longest survival after relapse of 6.6 months (95% CI, 5.3-8.0). Treatment differences remained significant in multivariable analysis adjusted for age and symptom duration in both diagnosis and relapse setting.

Conclusions: This study shows increased survival outcomes associated with radiation and chemotherapy treatment or a combination thereof, at diagnosis and relapse, in a historical DIPG cohort.

Background: Noninvasive prediction of H3K27M-altered Diffuse midline gliomas is important because of the involvement of deep locations and proximity to eloquent structures. We aim to predict H3K27M alteration in midline gliomas using radiomics features of T2W images.

Methods: Radiomics features extracted from 124 subjects (69 H3K27M-altered/55 H3K27M-wild type). T2W images were resampled to 1 × 1 × 1mm³ voxel size, preprocessed, and normalized for artifact correction, intensity variations. The feature set was normalized and subjected to reduction by variance thresholding, correlation coefficient thresholding, and sequential feature selector. Adaptive synthesis oversampling technique was used to oversample the training data. Random forest classifier (RFC), Decision tree classifier (DTC), and K-nearest neighbors classifier (KNN) were trained over the training dataset and the performance was assessed over the internal test dataset and external test data set (52 subjects: 33 H3K27M-altered/19-H3K27M-wild type).

Results: DTC achieved a validation score of 77.33% (5-fold cross-validation) and an accuracy of 80.64%, 75% on internal and external test datasets. RFC achieved a validation score of 80.7% (5-fold cross-validation) an accuracy of 80.6%, and 73% on internal and external test datasets. DTC achieved a validation score of 78.67% (5-fold cross-validation) an accuracy of 80.64%, and 61.53% on internal and external test datasets. The accuracy score of DTC, RFC, and KNN on the internal test dataset was approximately 80% while on the external test dataset, DTC achieved 75% accuracy, RFC achieved 73% accuracy and KNN achieved 65.1% accuracy.

Conclusions: H3K27M alteration is a potential immunotherapeutic marker and is associated with poor prognosis and radiomics features extracted from conventional T2W-images can help in identifying H3K27M-altered cases non-invasively with high precision.