The latest medical research on Neuro Oncology
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Request AccessCongress of Neurological Surgeons systematic review and evidence-based guidelines for the role of chemotherapy in newly diagnosed WHO Grade II diffuse glioma in adults: update.
Journal of Neuro-OncologyQuestions and recommendations from the prior version of these guidelines without changeTarget populationAdult patients (older than 18 years of age) with newly diagnosed World Health Organization (WHO) Grade II gliomas (Oligodendroglioma, astrocytoma, mixed oligoastrocytoma).QuestionIs there a role for chemotherapy as adjuvant therapy of choice in treatment of patients with newly diagnosed low-grade gliomas?RecommendationLevel III: Chemotherapy is recommended as a treatment option to postpone the use of radiotherapy, to slow tumor growth and to improve progression free survival (PFS), overall survival (OS) and clinical symptoms in adult patients with newly diagnosed LGG.QuestionWho are the patients with newly diagnosed LGG that would benefit the most from chemotherapy?RecommendationLevel III: Chemotherapy is recommended as an optional component alone or in combination with radiation as the initial adjuvant therapy for all patients who cannot undergo gross total resection (GTR) of a newly diagnosed LGG. Patients with residual tumor >1 cm on post-operative MRI, presenting diameter of 4 cm or older than 40 years of age should be considered for adjuvant therapy as well.QuestionAre there tumor markers that can predict which patients can benefit the most from initial treatment with chemotherapy?RecommendationLevel III: The addition of chemotherapy to standard RT is recommended in LGG patients that carry IDH mutation. In addition, temozolomide (TMZ) is recommended as a treatment option to slow tumor growth in patients who harbor the 1p/19q co-deletion.QuestionHow soon should the chemotherapy be started once the diagnosis of LGG is confirmed?RecommendationThere is insufficient evidence to make a definitive recommendation on the timing of starting chemotherapy after surgical/pathological diagnosis of LGG has been made. However, using the 12 weeks mark as the latest timeframe to start adjuvant chemotherapy is suggested. It is recommended that patients be enrolled in properly designed clinical trials to assess the timing of chemotherapy initiation once diagnosis is confirmed for this target population.QuestionWhat chemotherapeutic agents should be used for treatment of newly diagnosed LGG?RecommendationThere is insufficient evidence to make a recommendation of one particular regimen. Enrollment of subjects in properly designed trials comparing the efficacy of these or other agents is recommended so as to determine which of these regimens is superior.QuestionWhat is the optimal duration and dosing of chemotherapy as initial treatment for LGG?RecommendationInsufficient evidence exists regarding the duration of any specific cytotoxic drug regimen for treatment of newly diagnosed LGG. Enrollment of subjects in properly designed clinical investigations assessing the optimal duration of this therapy is recommended.QuestionShould chemotherapy be given alone or in conjunction with RT as initial therapy for LGG?RecommendationInsufficient evidence exists to make recommendations in this regard. Hence, enrollment of patients in properly designed clinical trials assessing the difference between chemotherapy alone, RT alone or a combination of them is recommended.QuestionShould chemotherapy be given in addition to other type of adjuvant therapy to patients with newly diagnosed LGG?RecommendationLevel II: It is recommended that chemotherapy be added to the RT in patients with unfavorable LGG to improve their progression free survival.Updated Question and Recommendations from the Prior Version of These GuidelinesQuestionIn adult patients with pathologically confirmed WHO Grade II diffuse glioma does chemotherapy alone, combined with radiation therapy or after radiation therapy compared to radiotherapy alone result in better overall survival, progression free survival, local control, fewer complications, neurocognitive preservation, and quality of life?RecommendationLevel I: It is recommended that chemotherapy (PCV) be added to radiation therapy (RT) in all patients with newly diagnosed high-risk WHO Grade II diffuse glioma (Patients younger than 40 unable to get gross total resection and older than 40 regardless of the degree of resection) to improve their overall survival.
It is suggested that chemotherapy alone should be considered in patients with newly diagnosed WHO Grade II diffuse glioma in cases with 1p/19q co-deletion.New questions and recommendationsTarget populationThese recommendations apply to adult patients diagnosed with WHO Grade II diffuse glioma.QuestionIn adult patients with newly diagnosed WHO grade II diffuse glioma does administration of chemotherapy prior to surgical resection improve extent of resection, provide longer progression free survival and overall survival when compared to chemotherapy alone?RecommendationLevel III: Neo-adjuvant temozolomide may be used in patients with WHO Grade II diffuse gliomas deemed unsafe for resection due to infiltration of eloquent areas or with large contralateral extension as an initial step to improve the extent of resection.There is insufficient evidence to support a recommendation regarding the ability of chemotherapy provided prior to surgical resection to improve progression free survival (PFS) and overall survival (OS).QuestionIn adult patients with newly diagnosed WHO grade II diffuse glioma does the administration of temozolomide increase the rate of malignant transformation when compared to no chemotherapy or other chemotherapy regimens?RecommendationThere is insufficient evidence to support a recommendation against the use of temozolomide for WHO Grade II diffuse gliomas due to concern over increasing the rate of malignant transformation.QuestionIn adult patients with newly diagnosed WHO grade II diffuse glioma does administration of multi-agent chemotherapy improve progression free survival and overall survival when compared to administration of single-agent chemotherapy?RecommendationThere is insufficient evidence to support a recommendation for or against the use of multi-agent chemotherapy to improve progression free survival and overall survival when compared to administration of single-agent chemotherapy in patients with newly diagnosed WHO Grade II diffuse glioma.
Neuroimmune-competent human brain organoid model of Diffuse Midline Glioma.
Neuro-OncologyPediatric high-grade gliomas, such as diffuse midline glioma (DMG), have a poor prognosis and lack curative treatments. Current research models of DMG primarily rely on human DMG cell lines cultured in vitro or xenografted into the brains of immunodeficient mice. However, these models are insufficient to recapitulate the complex cell-cell interactions between DMG and the tumor immune microenvironment (TIME), therefore fall short of accurately reflecting how efficacious therapeutic agents or combinations will be in the clinical setting.
To address these challenges, we developed a neuroimmune-competent brain/tumor fusion organoid model system consisting entirely of human cells to investigate the interactions between DMG cells and the primary innate immune cells of the brain, microglia, in the TIME at both cellular and subcellular levels. We generated microglia-containing brain organoids (MiCBO) that carry morphologically mature, motile microglia and multiple subtypes of neurons to mimic the brain tumor microenvironment. These organoids were then fused with H3K27M mutant, TP53P27R/K132R DMG tumor spheroids to create the MiCBO-tumor fusion (MiCBO-TF) model.
We utilized live imaging methods to simultaneously track the mobility of microglial cell bodies and the motility of their process, as well as the behavior of tumor cells within a human brain tissue environment. Our MiCBO-TF model faithfully recapitulated the diffuse infiltration pattern of DMG into brain tissue and revealed that microglial mobility and interactions with tumor cells are highly influenced by external factors and surrounding tissue environment.
The MiCBO-TF model represents a powerful platform for both mechanistic investigations and the development of precision medicine approaches for DMG.
Measurable disease as baseline criterion for response assessment in glioblastoma: A comparison of PET -based (PET RANO 1.0) and MRI-based (RANO) assessments.
Neuro-OncologyRecently, criteria based on amino acid positron emission tomography (PET) have been proposed for response assessment in diffuse gliomas (PET RANO 1.0). In this study, we compare the prevalence of measurable disease according to PET RANO 1.0 with magnetic resonance imaging (MRI)-based Response Assessment in Neuro-Oncology (RANO) criteria in glioblastoma.
We retrospectively identified patients with newly diagnosed IDH-wild-type glioblastoma who underwent [18F] Fluoroethyltyrosine (FET) PET and MRI after resection or biopsy and before radio-/radiochemotherapy. Two independent investigators analyzed measurable disease according to PET RANO 1.0 or MRI-RANO criteria. Additionally, lesion size, congruency patterns, and uptake intensity on [18F]FET PET images were assessed.
We evaluated 125 patients including 49 cases after primary resection and 76 cases after biopsy. Using PET criteria, 113 out of 125 patients (90.4%) had measurable disease, with a median PET-positive volume of 15.34 cm3 (8.83-38.03). With MRI, a significantly lower proportion of patients had measurable disease (57/125, 45.6%; P < .001) with a median sum of maximum cross-sectional diameters of 35.65 mm (26.18-45.98). None of the 12 patients without measurable disease on PET had measurable disease on MRI. Contrariwise, 56/68 patients (82.4%) without measurable disease on MRI exhibited measurable disease on PET. Clinical performance status correlated significantly with PET-positive volume and MRI-based sum of diameters (P < .0059, P < .0087, respectively).
[18F]FET PET identifies a higher number of patients with measurable disease compared to conventional MRI in newly diagnosed glioblastoma. PET-based assessment may serve as a novel baseline parameter for evaluating residual tumor burden and improving patient stratification in glioblastoma studies. Further validation in prospective trials is warranted.
Optimal treatment regimen for very elderly patients with atypical meningioma: an analysis of survival outcomes using the National Cancer Database (NCDB).
Journal of Neuro-OncologyWe assess the efficacy of different surgical resection types, radiotherapy, systemic therapy on overall survival in very elderly patients (age > 80) with intracranial atypical meningioma in contrast with their elderly (65-80) counterparts.
Patients > 65 years old with intracranial atypical meningiomas surgically resected and catalogued via the National Cancer Database were included. Cox proportional hazards models were developed to assess the association between surgical resection type, radiotherapy and systemic therapy with OS while controlling for sex, race, ethnicity, facility type, income, tumor size and CDCC score.
1747 elderly patients and 382 very elderly patients were included. 61.70% elderly patients and 58.90% very elderly patients received GTR. 26.50% elderly patients and 14.13% very elderly patients received radiotherapy. In multivariate analysis, subtotal resection is associated with worse survival (HR 1.28, p < 0.01) and radiotherapy is associated with improved survival (HR 0.76, p < 0.01). Systemic therapy was not associated with changes in survival outcomes (HR 1.17, p = 0.79). Using subgroup analysis, gross total resection is associated with better survival outcomes in both elderly and very elderly cohorts. Radiotherapy was not associated with improved survival (HR 0.85, p = 0.11) for patients between 65 and 80 years old, but was associated with improved survival (HR 0.51, p < 0.01) for patients > 80 years old.
GTR provides survival advantage in both elderly and very elderly cohorts. Radiotherapy provides survival benefits for very elderly patients even though very elderly patients are less likely to received radiotherapy. Very elderly patients may benefit from more aggressive management in the treatment of atypical meningiomas.
Multimodal treatment of glioblastoma with multiple lesions - a multi-center retrospective analysis.
Journal of Neuro-OncologyThe presence of multiple localizations (ML) in glioblastoma is rare and associated with perceived poor prognosis. The aim of this study is to evaluate the impact of a multimodal treatment on progression-free survival (PFS) and overall survival (OS) in ML glioblastoma.
Patients presenting with CNS WHO grade 4 glioblastoma with ML to 2 major German Departments of Neurosurgery between January 1st, 2008, to December 31st, 2020 were included in this study. Primary outcome parameters were extent of resection (EOR) using the 2021 RANO criteria, progression free- and overall survival.
A total of 483 patients with newly diagnosed glioblastoma (CNS WHO grade 4) were assessed. 134 patients presented with ML (72 multifocal (MF), 62 multicentric (MC)). The median PFS and OS did not differ among MC and MF glioblastomas. The EOR was a significant predictor of PFS and OS in ML glioblastoma. complete-, near total-, and subtotal resection significantly prolonged PFS (p < 0.0001) and OS (p < 0.0001) compared to biopsy alone. Standard radiotherapy (p = 0.045) and hypofractionated (p < 0.0001) radiotherapy and adjuvant treatment (Stupp protocol) prolonged PFS (p = 0.0012) and OS (p < 0.0001). In multivariate analysis Karnfosky performance score, EOR, and concomitant adjuvant treatment remained significant factors influencing OS. Propensity score matching of patients with ML and solitary lesion tumors showed similar PFS and OS (p = 0.08).
The presented data suggests that glioblastomas with multiple lesions treated with multimodal therapy equal survival rates compared to patients with solitary lesion tumors can be achieved. The results reflect the importance of an equally aggressive maximal treatment effort in this particular and often marginalized group of patients.
Predicting intraoperative 5-ALA-induced tumor fluorescence via MRI and deep learning in gliomas with radiographic lower-grade characteristics.
Journal of Neuro-OncologyLower-grade gliomas typically exhibit 5-aminolevulinic acid (5-ALA)-induced fluorescence in only 20-30% of cases, a rate that can be increased by doubling the administered dose of 5-ALA. Fluorescence can depict anaplastic foci, which can be precisely sampled to avoid undergrading. We aimed to analyze whether a deep learning model could predict intraoperative fluorescence based on preoperative magnetic resonance imaging (MRI).
We evaluated a cohort of 163 glioma patients categorized intraoperatively as fluorescent (n = 83) or non-fluorescent (n = 80). The preoperative MR images of gliomas lacking high-grade characteristics (e.g., necrosis or irregular ring contrast-enhancement) consisted of T1, T1-post gadolinium, and FLAIR sequences. The preprocessed MRIs were fed into an encoder-decoder convolutional neural network (U-Net), pre-trained for tumor segmentation using those three MRI sequences. We used the outputs of the bottleneck layer of the U-Net in the Variational Autoencoder (VAE) as features for classification. We identified and utilized the most effective features in a Random Forest classifier using the principal component analysis (PCA) and the partial least square discriminant analysis (PLS-DA) algorithms. We evaluated the performance of the classifier using a tenfold cross-validation procedure.
Our proposed approach's performance was assessed using mean balanced accuracy, mean sensitivity, and mean specificity. The optimal results were obtained by employing top-performing features selected by PCA, resulting in a mean balanced accuracy of 80% and mean sensitivity and specificity of 84% and 76%, respectively.
Our findings highlight the potential of a U-Net model, coupled with a Random Forest classifier, for pre-operative prediction of intraoperative fluorescence. We achieved high accuracy using the features extracted by the U-Net model pre-trained for brain tumor segmentation. While the model can still be improved, it has the potential for evaluating when to administer 5-ALA to gliomas lacking typical high-grade radiographic features.
Longitudinal multimodal profiling of IDH-wildtype glioblastoma reveals the molecular evolution and cellular phenotypes underlying prognostically different treatment responses.
Neuro-OncologyDespite recent advances in the biology of IDH-wildtype glioblastoma, it remains a devastating disease with median survival of less than 2 years. However, the molecular underpinnings of the heterogeneous response to the current standard-of-care treatment regimen consisting of maximal safe resection, adjuvant radiation, and chemotherapy with temozolomide remain unknown.
Comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent glioblastoma specimens from 106 patients was performed to investigate the molecular evolution and cellular phenotypes underlying differential treatment responses.
While TERT promoter mutation and CDKN2A homozygous deletion were early events during gliomagenesis shared by initial and recurrent tumors, most other recurrent genetic alterations (eg, EGFR, PTEN, and NF1) were commonly private to initial or recurrent tumors indicating acquisition later during clonal evolution. Furthermore, glioblastomas exhibited heterogeneous epigenomic evolution with subsets becoming more globally hypermethylated, hypomethylated, or remaining stable. Glioblastoma that underwent sarcomatous transformation had shorter interval to recurrence and were significantly enriched in NF1, TP53, and RB1 alterations and the mesenchymal epigenetic class. Patients who developed somatic hypermutation following temozolomide treatment had significantly longer interval to disease recurrence and prolonged overall survival, and increased methylation at 4 specific CpG sites in the promoter region of MGMT was significantly associated with this development of hypermutation. Finally, an epigenomic evolution signature incorporating change in DNA methylation levels across 347 critical CpG sites was developed that significantly correlated with clinical outcomes.
Glioblastoma undergoes heterogeneous genetic, epigenetic, and cellular evolution that underlies prognostically different treatment responses.
Phase 2 Trial of Veliparib, Local Irradiation and Temozolomide in Patients with Newly Diagnosed High-Grade Glioma: A Children's Oncology Group Study.
Neuro-OncologyThe outcome for pediatric patients with high-grade glioma (HGG) remains poor. Veliparib, a potent oral poly(adenosine diphosphate-ribose) polymerase (PARP) 1/2 inhibitor, enhances the activity of radiotherapy and DNA-damaging chemotherapy.
We conducted a single-arm, non-randomized phase 2 clinical trial to determine whether treatment with veliparib and radiotherapy, followed by veliparib and temozolomide, improves progression-free survival in pediatric patients with newly diagnosed HGG without H3 K27M or BRAF mutations compared to patient level data from historical cohorts with closely matching clinical and molecular features. Following surgical resection, newly diagnosed children with non-metastatic HGG were screened by rapid central pathology review and molecular testing. Eligible patients were enrolled on Stratum 1 (IDH wild-type) or Stratum 2 (IDH mutant).
Both strata were closed to accrual for futility after planned interim analyses. Among the 23 eligible patients who enrolled on Stratum 1 and received protocol therapy, the 1-year event-free survival (EFS) was 23% (standard error, SE = 9%) and 1-year overall survival (OS) was 64% (SE = 10%). Among the 14 eligible patients who enrolled on Stratum 2 and received protocol therapy, the 1-year EFS was 57% (SE = 13%) and 1-year OS was 93% (SE = 0.7%).
Rapid central pathology review and molecular testing for eligibility was feasible. The protocol therapy including radiation, veliparib and temozolomide was well tolerated but failed to improve outcome compared to clinically and molecularly matched historical control cohorts treated with higher doses of alkylator chemotherapy.
The impact of intraoperative mapping during re-resection in recurrent gliomas: a systematic review.
Journal of Neuro-OncologyPrevious evidence suggests that glioma re-resection can be effective in improving clinical outcomes. Furthermore, the use of mapping techniques during surgery has proven beneficial for newly diagnosed glioma patients. However, the effects of these mapping techniques during re-resection are not clear. This systematic review aimed to assess the evidence of using these techniques for recurrent glioma patients.
A systematic search was performed to identify relevant studies. Articles were eligible if they included adult patients with recurrent gliomas (WHO grade 2-4) who underwent re-resection. Study characteristics, application of mapping, and surgical outcome data on survival, patient functioning, and complications were extracted.
The literature strategy identified 6372 articles, of which 125 were screened for eligibility. After full-text evaluation, 58 articles were included in this review, comprising 5311 patients with re-resection for glioma. Of these articles, 17% (10/58) reported the use of awake or asleep intraoperative mapping techniques during re-resection. Mapping was applied in 5% (280/5311) of all patients, and awake craniotomy was used in 3% (142/5311) of the patients.
Mapping techniques can be used during re-resection, with some evidence that it is useful to improve clinical outcomes. However, there is a lack of high-quality support in the literature for using these techniques. The low number of studies reporting mapping techniques may, next to publication bias, reflect limited application in the recurrent setting. We advocate for future studies to determine their utility in reducing morbidity and increasing extent of resection, similar to their benefits in the primary setting.
Alternative lengthening of telomere-based immortalization renders H3G34R -mutant diffuse hemispheric glioma hypersensitive to PARP inhibitor combination regimens.
Neuro-OncologyDiffuse hemispheric glioma, H3G34R/V-mutant (DHG-H3G34) is characterized by poor prognosis and lack of effective treatment options. DHG-H3G34R further harbor deactivation of Alpha-Thalassemia/Mental Retardation Syndrome X-linked protein (ATRX; DHG-H3G34R_ATRX) suggesting a unique interaction of these two oncogenic alterations. In this study, we dissect their cell biological interplay, investigate the impact on telomere stabilization and, consequently, validate a targeted therapy approach.
We characterized patient-derived primary pediatric high-grade glioma (pHGG) models for telomere-maintenance mechanisms, DNA damage stress (including protein expression, pH2AX/Rad51 foci, cell-cycle arrest) and their sensitivity towards poly-ADP polymerase inhibitor (PARPi) combinations. Human induced pluripotent stem cells (iPSCs) were used for modelling the disease. The anticancer activity of PARPi combinations in vivo was studied in Chorioallantoic Membrane (CAM) and orthotopic in vivo experiments. Finally, we treated a DHG-H3G34R_ATRX patient with a PARPi combination therapy.
We elaborate that alternative lengthening of telomeres (ALT) is a key characteristic of DHG-H3G34R_ATRX. A dominant cooperative effect between H3G34R and ATRX loss in ALT activation also became apparent in iPSCs, which endogenously exert telomerase activity. In both, patient-derived DHG-H3G34R_ATRX models and H3G34R+/ATRX- iPSCs, the ALT phenotype was associated with increased basal DNA damage stress, mediating synergistic susceptibility towards PARPi (talazoparib, niraparib) combinations with topoisomerase-I inhibitors (topotecan, irinotecan). In a first-of-its-kind case, treatment of a DHG-H3G34R_ATRX patient with the brain-penetrant PARP inhibitor niraparib and topotecan resulted in a significant tumor reduction.
Our preclinical and clinical data strongly support the further development of PARPis together with DNA damage stress-inducing treatment regimens for DHG-H3G34R_ATRX.
The clinical impact of EGFR alterations in elderly glioblastoma patients: results from a real-life cohort.
Journal of Neuro-OncologyThe incidence of glioblastoma in the elderly population is increasing as the worldwide population ages. The differential and poorer survival in the elderly population compared to younger patients is partially explained. The present study aimed to investigate the clinical impact of epidermal growth factor receptor EGFR-altered glioblastoma in a real-life elderly glioblastoma population.
A bicentric and retrospective study was conducted. Patients were 70 years or older and suffering from histomolecularly confirmed glioblastoma. Single nucleotide variants (SNV), amplification, or chromosome 7 polysomy were sought. The primary endpoint was the comparison of overall survival (OS) in patients with or without EGFR alteration. Secondary objectives were to determine other clinical parameters correlated with EGFR alteration status.
Seventy-three patients were analyzed: 41.1% had at least one EGFR alteration. The presence of EGFR alteration did not impact overall survival: HR 0.97 [0.6-1.57], p = 0.9; the median overall survival was 6.5 months [5.3-9.3] in the EGFR-altered group versus 7 months [4.5-10] in the EGFR wild-type group, p = 0.75. In multivariate analysis, tumor resection was associated with a significant overall survival improvement: the median OS in the resected group (n = 20) was 11 months [95% CI 7.8-22] versus a median OS of 5.5 months [4.6-7.8] in the unresected group (n = 53), without correlation to EGFR alteration status.
In the modern era of molecular characterization and improved treatment modalities, the presence of at least one EGFR alteration did not influence survival outcomes in an elderly population of glioblastoma patients.
Clinical and Genetic Markers of Vascular Toxicity in Glioblastoma Patients: Insights from NRG Oncology RTOG-0825.
Neuro-OncologyGlioblastoma (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.
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.
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 (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 the SNP-dose effect (3 variants; OR: 3.79, p<.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<.0001).
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.
