Glioblastoma, IDH-Wildtype

MONDO:0850335 Pathograph 11 Show in embeddings browser diffuse glioma

Glioblastoma, IDH-wildtype, is the most common and aggressive primary malignant brain tumor in adults. Under WHO 2021 classification, this molecularly defined entity requires absence of IDH1/2 mutations and presence of at least one of three molecular features: TERT promoter mutation, EGFR amplification, or combined gain of chromosome 7 and loss of chromosome 10 (+7/-10). These tumors are characterized by rapid growth, extensive infiltration, florid microvascular proliferation, and necrosis. Despite multimodal therapy, prognosis remains poor with median survival of 14-16 months. Key molecular alterations include TERT promoter mutations (80%), EGFR amplification (40-50%), PTEN loss, and homozygous CDKN2A deletion.

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8
Pathophys.
1
Histopath.
5
Phenotypes
11
Pathograph
6
Genes
5
Medical Actions
3
Subtypes
3
Models
23
References
2
Deep Research
🏷

Classifications

ICD-O Morphology
Glioma
Harrison's Part
ONCOLOGY HEMATOLOGY
◆

Subtypes

3
Giant Cell Glioblastoma
Histological variant characterized by numerous bizarre multinucleated giant cells. May have slightly better prognosis than conventional glioblastoma. Often shows TP53 mutations.
Gliosarcoma
Variant with biphasic pattern showing areas of glial differentiation and malignant mesenchymal (sarcomatous) component. Similar prognosis to conventional glioblastoma. Sarcomatous component often shows divergent molecular features.
Epithelioid Glioblastoma
Aggressive variant with epithelioid morphology, frequent BRAF V600E mutations, and loss of INI1 expression. Often occurs in younger patients and may have worse prognosis than conventional glioblastoma.
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Pathophysiology

8
TERT Promoter Activation
TERT promoter mutations (C228T or C250T) occur in approximately 80% of IDH-wildtype glioblastomas. These mutations create de novo ETS transcription factor binding sites, leading to TERT upregulation and telomerase reactivation. This enables unlimited replicative potential and is a defining molecular feature.
astrocyte CL:0000127 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves astrocyte (CL:0000127). CL:0000127 is a cell type from the Cell Ontology.
telomere maintenance via telomerase GO:0007004 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased telomere maintenance via telomerase (GO:0007004). GO:0007004 is a biological process from the Gene Ontology. ↑ INCREASED
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Unlimited Replicative Potential Telomerase reactivation enables unlimited cell division
Show evidence (1 reference)
PMID:30333046 SUPPORT Human Clinical
"TERT promoter (TERTp) mutations are found in the majority of World Health Organization (WHO) grade IV adult IDH wild-type glioblastoma (IDH-wt GBM)."
Reports TERT promoter mutations in the majority of IDH-wildtype glioblastomas, supporting TERT promoter activation as a defining molecular feature.
Chromosome 7 Gain and Chromosome 10 Loss
Combined gain of chromosome 7 (+7) and loss of chromosome 10 (-10) is a defining molecular feature of IDH-wildtype glioblastoma, present in over 90% of cases. Chromosome 7 gain amplifies EGFR and MET. Chromosome 10 loss deletes PTEN and other tumor suppressors.
chromosome organization GO:0051276 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chromosome organization (GO:0051276). GO:0051276 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
EGFR/MET Pathway Activation Chromosome 7 gain increases EGFR and MET copy number
PTEN Tumor Suppressor Loss Chromosome 10 loss eliminates PTEN
EGFR/MET Pathway Activation
EGFR is amplified in 40-50% and MET in 5% of glioblastomas. EGFR amplification is often accompanied by EGFRvIII, a constitutively active deletion variant lacking exons 2-7. These alterations drive proliferation through RAS/RAF/MAPK and PI3K/AKT pathways.
MAPK cascade GO:0000165 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased MAPK cascade (GO:0000165). GO:0000165 is a biological process from the Gene Ontology. ↑ INCREASED phosphatidylinositol 3-kinase signaling GO:0043491 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased phosphatidylinositol 3-kinase signaling, annotated with phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491). GO:0043491 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Uncontrolled Cell Proliferation Receptor tyrosine kinase signaling drives tumor growth
PTEN Tumor Suppressor Loss
PTEN loss through chromosome 10 deletion, mutation, or epigenetic silencing occurs in 40-50% of glioblastomas. Loss of PTEN phosphatase activity leads to constitutive PI3K/AKT/mTOR pathway activation, promoting survival and growth.
negative regulation of phosphatidylinositol 3-kinase signaling GO:0051898 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of phosphatidylinositol 3-kinase signaling, annotated with negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898). GO:0051898 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
PI3K/AKT/mTOR Pathway Hyperactivation Loss of PTEN removes brake on PI3K signaling
PI3K/AKT/mTOR Pathway Hyperactivation
Constitutive PI3K/AKT/mTOR activation through EGFR amplification, PIK3CA/PIK3R1 mutation, or PTEN loss promotes cell survival, proliferation, metabolism, and angiogenesis. PIK3CA/PIK3R1 mutations are particularly enriched in the TERT promoter-wildtype subset of IDH-wildtype glioblastoma.
cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED apoptotic process GO:0006915 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (1 reference)
PMID:30333046 SUPPORT Human Clinical
"9 of 16 (56%) of TERTp-wt GBMs contained a PIK3CA or PIK3R1 mutation, while only 16/93 (17%) of TERTp-mutant GBMs harbored these alterations"
Reports PIK3CA/PIK3R1 mutations enriched in TERTp-wildtype IDH-wildtype glioblastomas (56%) compared to TERTp-mutant cases (17%), supporting recurrent PI3K pathway activation through somatic mutation in this disease.
Unlimited Replicative Potential
Telomerase reactivation through TERT promoter mutations enables glioblastoma cells to bypass replicative senescence and achieve unlimited proliferative capacity, a hallmark of cancer.
cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED
Uncontrolled Cell Proliferation
Multiple converging pathways (RTK signaling, PI3K/AKT/mTOR, cell cycle dysregulation) drive rapid proliferation characteristic of glioblastoma. High mitotic index and proliferation markers (Ki-67 often >20%) are typical.
astrocyte CL:0000127 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves astrocyte (CL:0000127). CL:0000127 is a cell type from the Cell Ontology.
cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED
Computational models
TumorTwin High-Grade Glioma Digital Twin DIGITAL TWIN TumorTwin (Python/PyTorch) The high-grade glioma case represents proliferative expansion through a spatial tumor-cell-density field and reports longitudinal total tumor cell count while applying modeled chemotherapy and radiotherapy effects.
Serial-MRI High-Grade Glioma Data-Assimilation Digital Twin DIGITAL TWIN The model represents spatially varying proliferation, invasion, and chemoradiotherapy response through enhancing and non-enhancing tumor-cell populations calibrated to serial MRI-derived cellularity.
M4RL Glioblastoma Tumor-Microenvironment Treatment Model AGENT BASED C++ multiscale agent-based model; Python/PyTorch PINN and A3C The model perturbs tumor-cell proliferation indirectly through simulated CSF1R inhibition of macrophage polarization and IGF1R inhibition of tumor cells, using tumor-cell density and predicted survival as optimization outputs.
M2-Like Tumor-Associated Macrophage Polarization
Glioblastoma-associated macrophages are biased toward protumorigenic, M2-like states that sustain an immunosuppressive tumor microenvironment and support tumor-cell proliferation, angiogenesis, and stem-like cell maintenance.
M2-like tumor-associated macrophage CL:0000890 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves M2-like tumor-associated macrophage, annotated with M2 macrophage (CL:0000890). CL:0000890 is a cell type from the Cell Ontology.
macrophage activation GO:0042116 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated macrophage activation (GO:0042116). GO:0042116 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Computational models
M4RL Glioblastoma Tumor-Microenvironment Treatment Model AGENT BASED C++ multiscale agent-based model; Python/PyTorch PINN and A3C The agent-based model explicitly represents M0, M1, and M2 macrophage states and perturbs their polarization through simulated CSF1R inhibition.
Downstream
Uncontrolled Cell Proliferation M2-like tumor-associated macrophages provide trophic and immune-evasion support for glioblastoma growth.
✶

Histopathology

1
Astrocytic Glioma VERY_FREQUENT
Glioblastoma is a malignant astrocytic glioma.
Show evidence (1 reference)
PMID:17974913 SUPPORT
"Malignant astrocytic gliomas such as glioblastoma are the most common and lethal"
Abstract groups glioblastoma among malignant astrocytic gliomas.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Glioblastoma, IDH-Wildtype Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

5
Headache VERY_FREQUENT Neurological HP:0002315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Headache (HP:0002315). HP:0002315 is a phenotype from the Human Phenotype Ontology.
Seizure FREQUENT Neurological HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24193082 SUPPORT Human Clinical
"Patients with malignant gliomas experience frequent clinical complications, including thromboembolic events, seizures, fluctuations in neurologic symptoms"
A clinical review identifies seizures as a frequent complication in patients with malignant gliomas including glioblastoma.
Cognitive Impairment FREQUENT Neurological HP:0100543 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cognitive impairment (HP:0100543). HP:0100543 is a phenotype from the Human Phenotype Ontology.
Focal Neurological Deficit FREQUENT Neurological HP:0001269 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemiparesis (HP:0001269). HP:0001269 is a phenotype from the Human Phenotype Ontology.
Personality Changes FREQUENT Neurological HP:0000751 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Personality changes (HP:0000751). HP:0000751 is a phenotype from the Human Phenotype Ontology.
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Genetic Associations

6
TERT (Promoter Mutation)
Gene: TERT hgnc:11730 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TERT (hgnc:11730). hgnc:11730 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:30333046 SUPPORT
"TERT promoter (TERTp) mutations are found in the majority of World Health Organization (WHO) grade IV adult IDH wild-type glioblastoma (IDH-wt GBM)."
Abstract reports TERT promoter mutations in the majority of IDH-wildtype glioblastomas.
EGFR (Amplification)
Gene: EGFR hgnc:3236 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EGFR (hgnc:3236). hgnc:3236 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:33235995 SUPPORT Human Clinical
"mGBM was defined as grade II-III IDH-wildtype astrocytoma without histological features of GBM but with one of the following molecular alterations: TERT mutation, EGFR amplification, or combination of whole chromosome 7 gain and whole chromosome 10 loss."
EGFR amplification is one of the molecular alterations that defines IDH-wildtype (molecular) glioblastoma.
PTEN (Loss/Mutation)
Gene: PTEN hgnc:9588 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PTEN (hgnc:9588). hgnc:9588 is a gene from the HUGO Gene Nomenclature Committee.
CDKN2A/CDKN2B (Homozygous Deletion)
Show evidence (1 reference)
PMID:33235995 SUPPORT Human Clinical
"CDKN2A/B deletion was associated with worse OS (HR 1.57, 95% CI 1.003-2.46) and PFS (HR 1.57, 95% CI 1.04-2.36) on MVA, but TERT mutation and EGFR amplification were not."
In a 367-patient IDH-wildtype GBM cohort, CDKN2A/B homozygous deletion was an independent adverse prognostic biomarker.
TP53 (Somatic Mutation)
Gene: TP53 hgnc:11998 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TP53 (hgnc:11998). hgnc:11998 is a gene from the HUGO Gene Nomenclature Committee.
NF1 (Somatic Mutation)
Gene: NF1 hgnc:7765 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NF1 (hgnc:7765). hgnc:7765 is a gene from the HUGO Gene Nomenclature Committee.
💊

Medical Actions

5
Maximal Safe Resection
Action: Gross Total ResectionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Gross Total Resection (NCIT:C131672). NCIT:C131672 is a clinical intervention from the NCI Thesaurus. NCIT:C131672
Aggressive surgical resection aims to maximize extent of resection while preserving neurological function. Greater extent of resection correlates with improved survival. Fluorescence-guided surgery with 5-ALA improves resection.
Radiation Therapy
Action: Radiation TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Radiation Therapy (NCIT:C15313). NCIT:C15313 is a clinical intervention from the NCI Thesaurus. NCIT:C15313
External beam radiation therapy (60 Gy in 30 fractions) is standard adjuvant treatment. Hypofractionated regimens may be used in elderly or poor performance status patients.
Temozolomide Chemotherapy
Action: chemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. Ontology label: Chemotherapy NCIT:C15632
Agent: temozolomide NCIT:C1244 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses temozolomide (NCIT:C1244). NCIT:C1244 is a therapeutic agent from the NCI Thesaurus.
Concurrent and adjuvant temozolomide (Stupp protocol) is standard of care. Temozolomide is an oral alkylating agent that crosses the blood-brain barrier. Benefit is greatest in MGMT methylated tumors.
Show evidence (1 reference)
NCIT:C1244 SUPPORT Other
"Temozolomide | Accepted_Therapeutic_Use_For | - | - | Malignant glioma (Anaplastic astrocytoma; Anaplastic oligodendrogliomas; Anaplastic oligoastrocytomas; Glioblastoma multiforme); Metastatic melanoma"
NCI Thesaurus asserts accepted therapeutic use of temozolomide for malignant glioma, including glioblastoma multiforme.
Tumor Treating Fields (TTFields)
Action: cranial electrical stimulationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cranial electrical stimulation (NCIT:C116561). NCIT:C116561 is a clinical intervention from the NCI Thesaurus. Ontology label: Cranial Electrical Stimulation NCIT:C116561
Alternating electric fields delivered via scalp arrays disrupt tumor cell mitosis. Added to maintenance temozolomide, TTFields extend median survival by approximately 5 months in newly diagnosed glioblastoma.
Bevacizumab
Action: immunotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunotherapy (NCIT:C15262). NCIT:C15262 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunotherapy NCIT:C15262
Agent: bevacizumab NCIT:C2039 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses bevacizumab (NCIT:C2039). NCIT:C2039 is a therapeutic agent from the NCI Thesaurus.
Anti-VEGF monoclonal antibody used for recurrent glioblastoma. Reduces peritumoral edema and steroid requirements but does not clearly extend overall survival. FDA approved for recurrent disease.
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Biochemical Markers

1
MGMT Promoter Methylation
🌍

Epidemiology

1
Most common primary malignant brain tumor
Glioblastoma is the most common and most malignant primary brain tumor in adults.
Show evidence (1 reference)
PMID:41569770 SUPPORT
"Glioblastoma, isocitrate dehydrogenase-wildtype CNS WHO grade 4 (formerly primary glioblastoma multiforme), is the most common and most malignant primary brain tumor."
This abstract explicitly identifies IDH-wildtype glioblastoma as the most common and most malignant primary brain tumor.
🧮

Computational Models

3
TumorTwin High-Grade Glioma Digital Twin Python/Jupyter Notebook/NIfTI TumorTwin (Python/PyTorch) DIGITAL_TWIN
Modular, differentiable Python framework for image-guided, patient-specific oncology digital twins. Its high-grade glioma demonstration calibrates an invasion, logistic-growth, chemotherapy, and radiotherapy model to longitudinal quantitative MRI-derived tumor-cell-density observations and forecasts spatial tumor growth and treatment response.
Repository ↗ PMID:42116079
Variable Model ID Unit Ontology Mappings Phenotype Thresholds
Normalized tumor cell density
Spatial tumor cellularity state bounded between zero and one.
 N dimensionless cell population proliferation
Total tumor cell count
Scalar tumor-burden output computed from normalized cell density and voxel cell capacity across the computational domain.
 TTC cells
Pathograph links
Uncontrolled Cell Proliferation partially recapitulates fidelity: low The high-grade glioma case represents proliferative expansion through a spatial tumor-cell-density field and reports longitudinal total tumor cell count while applying modeled chemotherapy and radiotherapy effects.
Limitations: The published package case is an idealized synthetic high-grade glioma demonstration, not a prospectively validated patient model. It is not stratified by the IDH-wildtype molecular criteria of this disease entry, assumes spatially homogeneous parameters, and is explicitly research-use software rather than clinical decision support.
Readouts
Longitudinal total tumor cell count
Interpretation: The simulated total tumor cell count trajectory summarizes the changing spatial tumor-cell-density field; it is a model output, not a validated clinical surrogate endpoint.
Show evidence (1 reference)
PMID:42116079 SUPPORT Computational
"Figure 3 shows a representative forward simulation for the model described in the previous section, showing both the TTC (Eq. (9)) over time, and 2D snapshots from the full 3D solution domain at specific timepoints."
Identifies total tumor cell count over time as an explicit output of the three-dimensional high-grade glioma simulation.
Show evidence (1 reference)
PMID:42116079 SUPPORT Computational
"We demonstrate the functionality of TumorTwin via an in silico dataset of high-grade glioma growth and response to radiation therapy."
Supports linking the framework to the proliferative growth node while also delimiting the evidence to an in-silico high-grade glioma case.
Findings
The package demonstrates end-to-end digital-twin calibration and prediction with a synthetic high-grade glioma growth and radiotherapy-response dataset.
Show evidence (1 reference)
PMID:42116079 SUPPORT Computational
"We demonstrate the functionality of TumorTwin via an in silico dataset of high-grade glioma growth and response to radiation therapy."
Directly states the disease-site demonstration and its synthetic scope.
Repository inspected at commit bedf90a6d47ba48cf5cdb25901967d84730061d1. The package uses the UT Austin Research License, which permits academic, research, experimental, and personal use but excludes commercial use and redistribution. At this revision, a Python 3.11 wheel installed and core imports plus the focused cellularity-estimation test passed, but the full upstream test suite failed during collection because of stale module imports.
Show evidence (1 reference)
PMID:42116079 SUPPORT Computational
"We present TumorTwin, a modular and differentiable software framework for initializing, updating, and leveraging patient-specific cancer tumor digital twins."
Establishes the identity and patient-specific digital-twin purpose of the software.
Serial-MRI High-Grade Glioma Data-Assimilation Digital Twin Reaction-diffusion PDE/MRI data-assimilation pipeline DIGITAL_TWIN
Patient-specific two-species reaction-diffusion model of enhancing and non-enhancing tumor regions. The platform repeatedly assimilates quantitative MRI-derived cell-density maps during chemoradiotherapy to update spatial tumor forecasts, and also evaluates longer forecasts initialized from two visits with patient-specific and cohort-derived parameters.
PMID:40730976
Variable Model ID Unit Ontology Mappings Phenotype Thresholds
Enhancing tumor-cell fraction
MRI-informed spatial state for the contrast-enhancing tumor population.
 Phi_E dimensionless
Non-enhancing tumor-cell fraction
MRI-informed spatial state for the non-enhancing T2-hyperintense tumor population.
 Phi_N dimensionless
Total tumor cell count
Combined enhancing and non-enhancing tumor-cell burden used for forecast evaluation.
 total_tumor_cell_count cells
Pathograph links
Uncontrolled Cell Proliferation partially recapitulates fidelity: moderate The model represents spatially varying proliferation, invasion, and chemoradiotherapy response through enhancing and non-enhancing tumor-cell populations calibrated to serial MRI-derived cellularity.
Limitations: The cohort contains 21 high-grade glioma cases, including 19 IDH-wildtype and two IDH-mutant tumors, so it is not a pure match to this disease entry. Weekly multiparametric MRI is not standard care, ADC is an imperfect proxy for tumor cellularity, and the reactive forecasting approach cannot predict de-novo tumor hotspots or explicitly model molecular and immune heterogeneity.
Readouts
Agreement of predicted and measured total tumor cell count
Interpretation: Concordance between predicted and MRI-derived total tumor cell counts evaluates how well the model tracks the proliferative tumor-burden trajectory during treatment; it is not a clinical outcome endpoint.
Show evidence (1 reference)
PMID:40730976 SUPPORT Computational
"concordance correlation coefficient (CCC) between the predicted and measured total tumor cell counts of 0.91"
Provides the median agreement metric for the repeatedly updated total tumor-cell-count forecasts.
Show evidence (1 reference)
PMID:40730976 SUPPORT Computational
"Tumor growth and response to chemoradiation was described using a two-species reaction-diffusion model of enhancing and non-enhancing regions of the tumor."
Establishes that proliferative tumor growth and treatment response are explicit components of the two-species spatial model.
Findings
Weekly data assimilation yielded a median total-cell-count concordance of 0.91 and median tumor-volume error of -2.6%; less frequently updated forecasts had lower concordance.
Show evidence (3 references)
PMID:40730976 SUPPORT Computational
"concordance correlation coefficient (CCC) between the predicted and measured total tumor cell counts of 0.91"
Supplies the weekly data-assimilation concordance metric.
PMID:40730976 SUPPORT Computational
"percent error in tumor volume of -2.6%"
Supplies the median weekly tumor-volume error.
PMID:40730976 SUPPORT Computational
"with significant differences between the approach (1) that does not use the cohort parameters and the two approaches (2 and 3) that do."
Supports the benefit of incorporating cohort information into the less-frequently updated forecasts.
No exact source-code repository was identified for this published model. TumorTwin is a related framework from the same modeling group but is curated separately above and must not be treated as the implementation of this study.
Show evidence (1 reference)
PMID:40730976 SUPPORT Computational
"We present a novel computational platform that assimilates MRI data to continually predict spatiotemporal tumor changes during chemoradiotherapy."
Establishes the continually updated, patient-specific forecasting platform.
M4RL Glioblastoma Tumor-Microenvironment Treatment Model C++/Python/CSV/PyTorch checkpoint (.pth) C++ multiscale agent-based model; Python/PyTorch PINN and A3C AGENT_BASED
Multiscale framework combining a spatial agent-based model of tumor cells, tumor-associated macrophages, cytokines, and intracellular ERK/AKT signaling with a Fokker-Planck physics-informed neural-network surrogate and A3C reinforcement learning to optimize CSF1R- and IGF1R-inhibitor scheduling.
Repository ↗ PMID:40779623
Variable Model ID Unit Ontology Mappings Phenotype Thresholds
Tumor-cell density
Normalized tumor-cell population state used by the surrogate and reinforcement-learning environment.
 c_T normalized density cell population proliferation
Predicted population survival probability
Population-level state and optimization outcome derived from modeled tumor-cell density.
 survival_probability probability
Pathograph links
M2-Like Tumor-Associated Macrophage Polarization perturbs fidelity: moderate The agent-based model explicitly represents M0, M1, and M2 macrophage states and perturbs their polarization through simulated CSF1R inhibition.
Limitations: The discrete M0/M1/M2 states simplify a continuous macrophage phenotype spectrum, and the treatment response was evaluated computationally and against preclinical rather than prospective patient data.
Readouts
M2-to-M1 macrophage repolarization under CSF1R inhibition
Direction: ALTERED
Interpretation: The simulated shift toward M1 macrophages is a direct readout of the model's macrophage-polarization mechanism, not evidence of clinical repolarization in patients.
Show evidence (1 reference)
PMID:40779623 SUPPORT Computational
"These CSF1R_I molecules initially blocks the binding of CSF1 to CSF1R on M2 macrophages, leading some M2 macrophages to polarize into M1 macrophages (Fig. 3A, day 50)."
Reports the simulated macrophage-state shift under CSF1R inhibition.
Show evidence (1 reference)
PMID:40779623 SUPPORT Computational
"We first develop a multiscale agent-based model (MSABM) for a critical biological scenario where interactions between tumor-associated macrophages (TAMs) and tumor cells (TCs) underlie immunotherapy resistance in glioblastoma."
Establishes tumor-associated macrophages as explicit mechanistic agents in the model.
Uncontrolled Cell Proliferation perturbs fidelity: moderate The model perturbs tumor-cell proliferation indirectly through simulated CSF1R inhibition of macrophage polarization and IGF1R inhibition of tumor cells, using tumor-cell density and predicted survival as optimization outputs.
Limitations: Validation is preclinical and computational rather than prospective or patient-specific, and the modeled glioblastoma is not stratified by IDH status. The agent model reduces macrophages to M0/M1/M2 states, omits T cells and other signaling pathways, and represents vasculature only as a source of recruited macrophages and drug penetration.
Readouts
Tumor-cell density under optimized combination treatment
Direction: DECREASED
Interpretation: Lower simulated tumor-cell density reports suppression of the modeled proliferative endpoint under the optimized schedule; it does not establish efficacy in people with IDH-wildtype glioblastoma.
Show evidence (1 reference)
PMID:40779623 SUPPORT Computational
"Accordingly, the Fokker-Planck equation–based surrogate model demonstrates that, under the most effective treatment scheduling, the predicted population’s TC density remains at a low level with a high probability (Fig. 8F)."
Reports the direction of the tumor-cell-density output under the reinforcement-learning-selected combination schedule.
Show evidence (1 reference)
PMID:40779623 SUPPORT Computational
"We first develop a multiscale agent-based model (MSABM) for a critical biological scenario where interactions between tumor-associated macrophages (TAMs) and tumor cells (TCs) underlie immunotherapy resistance in glioblastoma."
Establishes that tumor-cell and macrophage interactions are explicitly represented in the glioblastoma agent-based model.
Findings
The selected four-week-interval policy combined continuous CSF1R inhibition ending after week 20 with continuous IGF1R inhibition beginning at week 5.
Show evidence (1 reference)
PMID:40779623 SUPPORT Computational
"By the above procedures, we identified the optimal treatment involving continuous use of CSF1R_I ending after week 20, combined with continuous use of IGF1R_I starting from week 5."
Directly states the reinforcement-learning-selected treatment schedule.
Repository inspected at commit 3f64a2cbeb6797cd281c19d70a838282996f62b2. The three core multiscale agent-based targets compiled after explicitly selecting C++11, and all four Python scripts passed syntax compilation. The spatial-transcriptomic C++ target did not compile because OpenMP was not declared, and no dependency manifest or license file was present.
Show evidence (1 reference)
PMID:40779623 SUPPORT Computational
"Here, we describe a multiscale mathematical model-informed reinforcement learning (M4RL) framework to simulate dynamic tumor-microenvironment interactions and optimize drug combination scheduling."
Establishes the composition and optimization purpose of the computational framework.
{ }

Source YAML

click to show 
name: Glioblastoma, IDH-Wildtype
creation_date: '2026-01-26T02:55:13Z'
description: >-
  Glioblastoma, IDH-wildtype, is the most common and aggressive primary malignant
  brain tumor in adults. Under WHO 2021 classification, this molecularly defined
  entity requires absence of IDH1/2 mutations and presence of at least one of three
  molecular features: TERT promoter mutation, EGFR amplification, or combined gain
  of chromosome 7 and loss of chromosome 10 (+7/-10). These tumors are characterized
  by rapid growth, extensive infiltration, florid microvascular proliferation, and
  necrosis. Despite multimodal therapy, prognosis remains poor with median survival
  of 14-16 months. Key molecular alterations include TERT promoter mutations (80%),
  EGFR amplification (40-50%), PTEN loss, and homozygous CDKN2A deletion.
categories:
- Central Nervous System Neoplasm
- Adult Brain Tumor
- Molecularly Defined Tumor
- High-Grade Glioma
parents:
- diffuse glioma
epidemiology:
- name: Most common primary malignant brain tumor
  description: Glioblastoma is the most common and most malignant primary brain tumor in adults.
  evidence:
  - reference: PMID:41569770
    reference_title: "Glioblastoma eroding through falx cerebri: a rarity or commonly seen? Illustrative case."
    supports: SUPPORT
    snippet: Glioblastoma, isocitrate dehydrogenase-wildtype CNS WHO grade 4 (formerly primary glioblastoma multiforme), is the most common and most malignant primary brain tumor.
    explanation: This abstract explicitly identifies IDH-wildtype glioblastoma as the most common and most malignant primary brain tumor.
has_subtypes:
- name: Giant Cell Glioblastoma
  description: >-
    Histological variant characterized by numerous bizarre multinucleated giant cells.
    May have slightly better prognosis than conventional glioblastoma. Often shows
    TP53 mutations.
- name: Gliosarcoma
  description: >-
    Variant with biphasic pattern showing areas of glial differentiation and
    malignant mesenchymal (sarcomatous) component. Similar prognosis to conventional
    glioblastoma. Sarcomatous component often shows divergent molecular features.
- name: Epithelioid Glioblastoma
  description: >-
    Aggressive variant with epithelioid morphology, frequent BRAF V600E mutations,
    and loss of INI1 expression. Often occurs in younger patients and may have
    worse prognosis than conventional glioblastoma.
pathophysiology:
- name: TERT Promoter Activation
  conforms_to: "enabling_replicative_immortality#Telomere Maintenance Reactivation"
  description: >-
    TERT promoter mutations (C228T or C250T) occur in approximately 80% of
    IDH-wildtype glioblastomas. These mutations create de novo ETS transcription
    factor binding sites, leading to TERT upregulation and telomerase reactivation.
    This enables unlimited replicative potential and is a defining molecular feature.
  evidence:
  - reference: PMID:30333046
    reference_title: "TERT promoter wild-type glioblastomas show distinct clinical features and frequent PI3K pathway mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TERT promoter (TERTp) mutations are found in the majority of World Health Organization (WHO) grade IV adult IDH wild-type glioblastoma (IDH-wt GBM)."
    explanation: Reports TERT promoter mutations in the majority of IDH-wildtype glioblastomas, supporting TERT promoter activation as a defining molecular feature.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: telomere maintenance via telomerase
    modifier: INCREASED
    term:
      id: GO:0007004
      label: telomere maintenance via telomerase
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  downstream:
  - target: Unlimited Replicative Potential
    description: Telomerase reactivation enables unlimited cell division
- name: Chromosome 7 Gain and Chromosome 10 Loss
  conforms_to: "genome_instability_mutation#Mutator Phenotype and Chromosomal Instability"
  description: >-
    Combined gain of chromosome 7 (+7) and loss of chromosome 10 (-10) is a
    defining molecular feature of IDH-wildtype glioblastoma, present in over 90%
    of cases. Chromosome 7 gain amplifies EGFR and MET. Chromosome 10 loss deletes
    PTEN and other tumor suppressors.
  biological_processes:
  - preferred_term: chromosome organization
    modifier: ABNORMAL
    term:
      id: GO:0051276
      label: chromosome organization
  downstream:
  - target: EGFR/MET Pathway Activation
    description: Chromosome 7 gain increases EGFR and MET copy number
  - target: PTEN Tumor Suppressor Loss
    description: Chromosome 10 loss eliminates PTEN
- name: EGFR/MET Pathway Activation
  conforms_to: "sustaining_proliferative_signaling#Constitutive Mitogenic Pathway Activation"
  description: >-
    EGFR is amplified in 40-50% and MET in 5% of glioblastomas. EGFR amplification
    is often accompanied by EGFRvIII, a constitutively active deletion variant
    lacking exons 2-7. These alterations drive proliferation through RAS/RAF/MAPK
    and PI3K/AKT pathways.
  biological_processes:
  - preferred_term: MAPK cascade
    modifier: INCREASED
    term:
      id: GO:0000165
      label: MAPK cascade
  - preferred_term: phosphatidylinositol 3-kinase signaling
    modifier: INCREASED
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
  downstream:
  - target: Uncontrolled Cell Proliferation
    description: Receptor tyrosine kinase signaling drives tumor growth
- name: PTEN Tumor Suppressor Loss
  conforms_to: "sustaining_proliferative_signaling#Oncogenic Growth-Signal Lesion"
  description: >-
    PTEN loss through chromosome 10 deletion, mutation, or epigenetic silencing
    occurs in 40-50% of glioblastomas. Loss of PTEN phosphatase activity leads to
    constitutive PI3K/AKT/mTOR pathway activation, promoting survival and growth.
  biological_processes:
  - preferred_term: negative regulation of phosphatidylinositol 3-kinase signaling
    modifier: DECREASED
    term:
      id: GO:0051898
      label: negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
  downstream:
  - target: PI3K/AKT/mTOR Pathway Hyperactivation
    description: Loss of PTEN removes brake on PI3K signaling
- name: PI3K/AKT/mTOR Pathway Hyperactivation
  description: >-
    Constitutive PI3K/AKT/mTOR activation through EGFR amplification, PIK3CA/PIK3R1 mutation,
    or PTEN loss promotes cell survival, proliferation, metabolism, and angiogenesis.
    PIK3CA/PIK3R1 mutations are particularly enriched in the TERT promoter-wildtype subset
    of IDH-wildtype glioblastoma.
  evidence:
  - reference: PMID:30333046
    reference_title: "TERT promoter wild-type glioblastomas show distinct clinical features and frequent PI3K pathway mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "9 of 16 (56%) of TERTp-wt GBMs contained a PIK3CA or PIK3R1 mutation, while only 16/93 (17%) of TERTp-mutant GBMs harbored these alterations"
    explanation: Reports PIK3CA/PIK3R1 mutations enriched in TERTp-wildtype IDH-wildtype glioblastomas (56%) compared to TERTp-mutant cases (17%), supporting recurrent PI3K pathway activation through somatic mutation in this disease.
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  - preferred_term: apoptotic process
    modifier: DECREASED
    term:
      id: GO:0006915
      label: apoptotic process
- name: Unlimited Replicative Potential
  conforms_to: "enabling_replicative_immortality#Replicative Immortality"
  description: >-
    Telomerase reactivation through TERT promoter mutations enables glioblastoma
    cells to bypass replicative senescence and achieve unlimited proliferative
    capacity, a hallmark of cancer.
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
- name: Uncontrolled Cell Proliferation
  description: >-
    Multiple converging pathways (RTK signaling, PI3K/AKT/mTOR, cell cycle
    dysregulation) drive rapid proliferation characteristic of glioblastoma.
    High mitotic index and proliferation markers (Ki-67 often >20%) are typical.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
- name: M2-Like Tumor-Associated Macrophage Polarization
  description: >-
    Glioblastoma-associated macrophages are biased toward protumorigenic,
    M2-like states that sustain an immunosuppressive tumor microenvironment and
    support tumor-cell proliferation, angiogenesis, and stem-like cell
    maintenance.
  cell_types:
  - preferred_term: M2-like tumor-associated macrophage
    term:
      id: CL:0000890
      label: M2 macrophage
  biological_processes:
  - preferred_term: macrophage activation
    modifier: DYSREGULATED
    term:
      id: GO:0042116
      label: macrophage activation
  conforms_to: "tumor_promoting_inflammation#Pro-Tumorigenic Inflammatory Microenvironment"
  downstream:
  - target: Uncontrolled Cell Proliferation
    description: M2-like tumor-associated macrophages provide trophic and immune-evasion support for glioblastoma growth.
    evidence:
    - reference: PMID:42383800
      reference_title: "Targeting the Tumor Immune Ecosystem in Glioblastoma: Challenges and Innovations in Immunotherapy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Tumor-associated macrophages (TAMs), particularly those with an M2-like phenotype, sustain GBM proliferation, angiogenesis, and stem-like cell maintenance."
      explanation: A recent review directly links M2-like tumor-associated macrophages to glioblastoma proliferation and other protumorigenic capabilities.
histopathology:
- name: Astrocytic Glioma
  finding_term:
    preferred_term: Astrocytoma
    term:
      id: NCIT:C60781
      label: Astrocytoma
  frequency: VERY_FREQUENT
  description: Glioblastoma is a malignant astrocytic glioma.
  evidence:
  - reference: PMID:17974913
    reference_title: "Malignant astrocytic glioma: genetics, biology, and paths to treatment."
    supports: SUPPORT
    snippet: "Malignant astrocytic gliomas such as glioblastoma are the most common and lethal"
    explanation: Abstract groups glioblastoma among malignant astrocytic gliomas.

phenotypes:
- category: Neurological
  name: Headache
  frequency: VERY_FREQUENT
  description: >-
    Headache from mass effect and increased intracranial pressure is common,
    often progressive and worse in the morning.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
- category: Neurological
  name: Seizure
  frequency: FREQUENT
  description: >-
    Seizures occur in 25-40% of patients, more commonly with cortical involvement.
    May be focal or generalized.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:24193082
    reference_title: "Glioblastoma and other malignant gliomas: a clinical review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with malignant gliomas experience frequent clinical complications, including thromboembolic events, seizures, fluctuations in neurologic symptoms"
    explanation: A clinical review identifies seizures as a frequent complication in patients with malignant gliomas including glioblastoma.
- category: Neurological
  name: Cognitive Impairment
  frequency: FREQUENT
  description: >-
    Progressive cognitive decline including memory, attention, and executive
    function deficits.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
- category: Neurological
  name: Focal Neurological Deficit
  frequency: FREQUENT
  description: >-
    Motor weakness, sensory changes, aphasia, or visual field deficits depending
    on tumor location. Often progresses rapidly.
  phenotype_term:
    preferred_term: Hemiparesis
    term:
      id: HP:0001269
      label: Hemiparesis
- category: Neurological
  name: Personality Changes
  frequency: FREQUENT
  description: >-
    Personality and behavioral changes, particularly with frontal lobe involvement.
    May include apathy, disinhibition, or emotional lability.
  phenotype_term:
    preferred_term: Personality changes
    term:
      id: HP:0000751
      label: Personality changes
genetic:
- name: TERT
  gene_term:
    preferred_term: TERT
    term:
      id: hgnc:11730
      label: TERT
  association: Promoter Mutation
  notes: >-
    TERT promoter mutations (C228T or C250T) occur in approximately 80% of
    IDH-wildtype glioblastomas. Creates ETS binding sites leading to telomerase
    reactivation. One of three defining molecular features for diagnosis.
  evidence:
  - reference: PMID:30333046
    reference_title: "TERT promoter wild-type glioblastomas show distinct clinical features and frequent PI3K pathway mutations."
    supports: SUPPORT
    snippet: "TERT promoter (TERTp) mutations are found in the majority of World Health Organization (WHO) grade IV adult IDH wild-type glioblastoma (IDH-wt GBM)."
    explanation: "Abstract reports TERT promoter mutations in the majority of IDH-wildtype glioblastomas."
- name: EGFR
  gene_term:
    preferred_term: EGFR
    term:
      id: hgnc:3236
      label: EGFR
  association: Amplification
  notes: >-
    EGFR amplification occurs in 40-50% of cases. EGFRvIII variant (deletion of
    exons 2-7) present in approximately 50% of EGFR-amplified tumors. EGFR
    amplification is one of three defining molecular features.
  evidence:
  - reference: PMID:33235995
    reference_title: "Prognostic impact of CDKN2A/B deletion, TERT mutation, and EGFR amplification on histological and molecular IDH-wildtype glioblastoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mGBM was defined as grade II-III IDH-wildtype astrocytoma without histological features of GBM but with one of the following molecular alterations: TERT mutation, EGFR amplification, or combination of whole chromosome 7 gain and whole chromosome 10 loss."
    explanation: EGFR amplification is one of the molecular alterations that defines IDH-wildtype (molecular) glioblastoma.
- name: PTEN
  gene_term:
    preferred_term: PTEN
    term:
      id: hgnc:9588
      label: PTEN
  association: Loss/Mutation
  notes: >-
    PTEN is lost or mutated in 40-50% of glioblastomas through chromosome 10 loss,
    mutation, or promoter methylation. Loss activates PI3K/AKT signaling.
- name: CDKN2A/CDKN2B
  association: Homozygous Deletion
  notes: >-
    Homozygous deletion of CDKN2A/CDKN2B at 9p21 occurs in approximately 60% of
    glioblastomas. Eliminates p16INK4a and p14ARF tumor suppressors, disrupting
    both RB and p53 pathways.
  evidence:
  - reference: PMID:33235995
    reference_title: "Prognostic impact of CDKN2A/B deletion, TERT mutation, and EGFR amplification on histological and molecular IDH-wildtype glioblastoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CDKN2A/B deletion was associated with worse OS (HR 1.57, 95% CI 1.003-2.46) and PFS (HR 1.57, 95% CI 1.04-2.36) on MVA, but TERT mutation and EGFR amplification were not."
    explanation: In a 367-patient IDH-wildtype GBM cohort, CDKN2A/B homozygous deletion was an independent adverse prognostic biomarker.
- name: TP53
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  association: Somatic Mutation
  notes: >-
    TP53 mutations occur in approximately 30% of IDH-wildtype glioblastomas,
    less common than in IDH-mutant tumors.
- name: NF1
  gene_term:
    preferred_term: NF1
    term:
      id: hgnc:7765
      label: NF1
  association: Somatic Mutation
  notes: >-
    NF1 mutations occur in approximately 10-15% of glioblastomas, activating
    RAS/MAPK signaling. More common in mesenchymal subtype.
biochemical:
- name: MGMT Promoter Methylation
  notes: >-
    MGMT promoter methylation occurs in approximately 35-45% of glioblastomas and
    predicts response to temozolomide. Silencing of MGMT DNA repair enzyme improves
    sensitivity to alkylating chemotherapy.
computational_models:
- name: TumorTwin High-Grade Glioma Digital Twin
  description: >-
    Modular, differentiable Python framework for image-guided, patient-specific
    oncology digital twins. Its high-grade glioma demonstration calibrates an
    invasion, logistic-growth, chemotherapy, and radiotherapy model to longitudinal
    quantitative MRI-derived tumor-cell-density observations and forecasts spatial
    tumor growth and treatment response.
  model_type: DIGITAL_TWIN
  repository_url: https://github.com/OncologyModelingGroup/TumorTwin
  model_id: "GitHub:OncologyModelingGroup/TumorTwin@bedf90a6d47ba48cf5cdb25901967d84730061d1"
  model_software: TumorTwin (Python/PyTorch)
  model_format: Python/Jupyter Notebook/NIfTI
  publication: PMID:42116079
  modeled_mechanisms:
  - target: Uncontrolled Cell Proliferation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      The high-grade glioma case represents proliferative expansion through a
      spatial tumor-cell-density field and reports longitudinal total tumor cell
      count while applying modeled chemotherapy and radiotherapy effects.
    limitations: >-
      The published package case is an idealized synthetic high-grade glioma
      demonstration, not a prospectively validated patient model. It is not
      stratified by the IDH-wildtype molecular criteria of this disease entry,
      assumes spatially homogeneous parameters, and is explicitly research-use
      software rather than clinical decision support.
    readouts:
    - name: Longitudinal total tumor cell count
      target: Uncontrolled Cell Proliferation
      interpretation: >-
        The simulated total tumor cell count trajectory summarizes the changing
        spatial tumor-cell-density field; it is a model output, not a validated
        clinical surrogate endpoint.
      evidence:
      - reference: PMID:42116079
        reference_title: "TumorTwin: a Python framework for patient-specific digital twins in oncology."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: "Figure 3 shows a representative forward simulation for the model described in the previous section, showing both the TTC (Eq. (9)) over time, and 2D snapshots from the full 3D solution domain at specific timepoints."
        explanation: >-
          Identifies total tumor cell count over time as an explicit output of the
          three-dimensional high-grade glioma simulation.
    evidence:
    - reference: PMID:42116079
      reference_title: "TumorTwin: a Python framework for patient-specific digital twins in oncology."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "We demonstrate the functionality of TumorTwin via an in silico dataset of high-grade glioma growth and response to radiation therapy."
      explanation: >-
        Supports linking the framework to the proliferative growth node while
        also delimiting the evidence to an in-silico high-grade glioma case.
  variables:
  - name: Normalized tumor cell density
    dataset_identifier: N
    description: Spatial tumor cellularity state bounded between zero and one.
    unit: dimensionless
    mappings_list:
    - preferred_term: cell population proliferation
      term:
        id: GO:0008283
        label: cell population proliferation
  - name: Total tumor cell count
    dataset_identifier: TTC
    description: >-
      Scalar tumor-burden output computed from normalized cell density and voxel
      cell capacity across the computational domain.
    unit: cells
  findings:
  - statement: >-
      The package demonstrates end-to-end digital-twin calibration and prediction
      with a synthetic high-grade glioma growth and radiotherapy-response dataset.
    evidence:
    - reference: PMID:42116079
      reference_title: "TumorTwin: a Python framework for patient-specific digital twins in oncology."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "We demonstrate the functionality of TumorTwin via an in silico dataset of high-grade glioma growth and response to radiation therapy."
      explanation: >-
        Directly states the disease-site demonstration and its synthetic scope.
  evidence:
  - reference: PMID:42116079
    reference_title: "TumorTwin: a Python framework for patient-specific digital twins in oncology."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "We present TumorTwin, a modular and differentiable software framework for initializing, updating, and leveraging patient-specific cancer tumor digital twins."
    explanation: Establishes the identity and patient-specific digital-twin purpose of the software.
  notes: >-
    Repository inspected at commit bedf90a6d47ba48cf5cdb25901967d84730061d1.
    The package uses the UT Austin Research License, which permits academic,
    research, experimental, and personal use but excludes commercial use and
    redistribution. At this revision, a Python 3.11 wheel installed and core
    imports plus the focused cellularity-estimation test passed, but the full
    upstream test suite failed during collection because of stale module imports.
- name: Serial-MRI High-Grade Glioma Data-Assimilation Digital Twin
  description: >-
    Patient-specific two-species reaction-diffusion model of enhancing and
    non-enhancing tumor regions. The platform repeatedly assimilates quantitative
    MRI-derived cell-density maps during chemoradiotherapy to update spatial tumor
    forecasts, and also evaluates longer forecasts initialized from two visits
    with patient-specific and cohort-derived parameters.
  model_type: DIGITAL_TWIN
  model_id: "PMID:40730976#two-species-data-assimilation"
  model_format: Reaction-diffusion PDE/MRI data-assimilation pipeline
  publication: PMID:40730976
  modeled_mechanisms:
  - target: Uncontrolled Cell Proliferation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The model represents spatially varying proliferation, invasion, and
      chemoradiotherapy response through enhancing and non-enhancing tumor-cell
      populations calibrated to serial MRI-derived cellularity.
    limitations: >-
      The cohort contains 21 high-grade glioma cases, including 19 IDH-wildtype
      and two IDH-mutant tumors, so it is not a pure match to this disease entry.
      Weekly multiparametric MRI is not standard care, ADC is an imperfect proxy
      for tumor cellularity, and the reactive forecasting approach cannot predict
      de-novo tumor hotspots or explicitly model molecular and immune heterogeneity.
    readouts:
    - name: Agreement of predicted and measured total tumor cell count
      target: Uncontrolled Cell Proliferation
      interpretation: >-
        Concordance between predicted and MRI-derived total tumor cell counts
        evaluates how well the model tracks the proliferative tumor-burden
        trajectory during treatment; it is not a clinical outcome endpoint.
      evidence:
      - reference: PMID:40730976
        reference_title: "A data assimilation framework for predicting the spatiotemporal response of high-grade gliomas to chemoradiation."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: "concordance correlation coefficient (CCC) between the predicted and measured total tumor cell counts of 0.91"
        explanation: >-
          Provides the median agreement metric for the repeatedly updated total
          tumor-cell-count forecasts.
    evidence:
    - reference: PMID:40730976
      reference_title: "A data assimilation framework for predicting the spatiotemporal response of high-grade gliomas to chemoradiation."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "Tumor growth and response to chemoradiation was described using a two-species reaction-diffusion model of enhancing and non-enhancing regions of the tumor."
      explanation: >-
        Establishes that proliferative tumor growth and treatment response are
        explicit components of the two-species spatial model.
  variables:
  - name: Enhancing tumor-cell fraction
    dataset_identifier: Phi_E
    description: MRI-informed spatial state for the contrast-enhancing tumor population.
    unit: dimensionless
  - name: Non-enhancing tumor-cell fraction
    dataset_identifier: Phi_N
    description: MRI-informed spatial state for the non-enhancing T2-hyperintense tumor population.
    unit: dimensionless
  - name: Total tumor cell count
    dataset_identifier: total_tumor_cell_count
    description: Combined enhancing and non-enhancing tumor-cell burden used for forecast evaluation.
    unit: cells
  findings:
  - statement: >-
      Weekly data assimilation yielded a median total-cell-count concordance of
      0.91 and median tumor-volume error of -2.6%; less frequently updated
      forecasts had lower concordance.
    evidence:
    - reference: PMID:40730976
      reference_title: "A data assimilation framework for predicting the spatiotemporal response of high-grade gliomas to chemoradiation."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "concordance correlation coefficient (CCC) between the predicted and measured total tumor cell counts of 0.91"
      explanation: Supplies the weekly data-assimilation concordance metric.
    - reference: PMID:40730976
      reference_title: "A data assimilation framework for predicting the spatiotemporal response of high-grade gliomas to chemoradiation."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "percent error in tumor volume of -2.6%"
      explanation: Supplies the median weekly tumor-volume error.
    - reference: PMID:40730976
      reference_title: "A data assimilation framework for predicting the spatiotemporal response of high-grade gliomas to chemoradiation."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "with significant differences between the approach (1) that does not use the cohort parameters and the two approaches (2 and 3) that do."
      explanation: >-
        Supports the benefit of incorporating cohort information into the
        less-frequently updated forecasts.
  evidence:
  - reference: PMID:40730976
    reference_title: "A data assimilation framework for predicting the spatiotemporal response of high-grade gliomas to chemoradiation."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "We present a novel computational platform that assimilates MRI data to continually predict spatiotemporal tumor changes during chemoradiotherapy."
    explanation: Establishes the continually updated, patient-specific forecasting platform.
  notes: >-
    No exact source-code repository was identified for this published model.
    TumorTwin is a related framework from the same modeling group but is curated
    separately above and must not be treated as the implementation of this study.
- name: M4RL Glioblastoma Tumor-Microenvironment Treatment Model
  description: >-
    Multiscale framework combining a spatial agent-based model of tumor cells,
    tumor-associated macrophages, cytokines, and intracellular ERK/AKT signaling
    with a Fokker-Planck physics-informed neural-network surrogate and A3C
    reinforcement learning to optimize CSF1R- and IGF1R-inhibitor scheduling.
  model_type: AGENT_BASED
  repository_url: https://github.com/SunXQlab/M4RL
  model_id: "GitHub:SunXQlab/M4RL@3f64a2cbeb6797cd281c19d70a838282996f62b2"
  model_software: C++ multiscale agent-based model; Python/PyTorch PINN and A3C
  model_format: C++/Python/CSV/PyTorch checkpoint (.pth)
  publication: PMID:40779623
  modeled_mechanisms:
  - target: M2-Like Tumor-Associated Macrophage Polarization
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      The agent-based model explicitly represents M0, M1, and M2 macrophage
      states and perturbs their polarization through simulated CSF1R inhibition.
    limitations: >-
      The discrete M0/M1/M2 states simplify a continuous macrophage phenotype
      spectrum, and the treatment response was evaluated computationally and
      against preclinical rather than prospective patient data.
    readouts:
    - name: M2-to-M1 macrophage repolarization under CSF1R inhibition
      target: M2-Like Tumor-Associated Macrophage Polarization
      direction: ALTERED
      interpretation: >-
        The simulated shift toward M1 macrophages is a direct readout of the
        model's macrophage-polarization mechanism, not evidence of clinical
        repolarization in patients.
      evidence:
      - reference: PMID:40779623
        reference_title: "Multiscale mathematical model-informed reinforcement learning optimizes combination treatment scheduling in glioblastoma evolution."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: "These CSF1R_I molecules initially blocks the binding of CSF1 to CSF1R on M2 macrophages, leading some M2 macrophages to polarize into M1 macrophages (Fig. 3A, day 50)."
        explanation: Reports the simulated macrophage-state shift under CSF1R inhibition.
    evidence:
    - reference: PMID:40779623
      reference_title: "Multiscale mathematical model-informed reinforcement learning optimizes combination treatment scheduling in glioblastoma evolution."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "We first develop a multiscale agent-based model (MSABM) for a critical biological scenario where interactions between tumor-associated macrophages (TAMs) and tumor cells (TCs) underlie immunotherapy resistance in glioblastoma."
      explanation: Establishes tumor-associated macrophages as explicit mechanistic agents in the model.
  - target: Uncontrolled Cell Proliferation
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      The model perturbs tumor-cell proliferation indirectly through simulated
      CSF1R inhibition of macrophage polarization and IGF1R inhibition of tumor
      cells, using tumor-cell density and predicted survival as optimization
      outputs.
    limitations: >-
      Validation is preclinical and computational rather than prospective or
      patient-specific, and the modeled glioblastoma is not stratified by IDH
      status. The agent model reduces macrophages to M0/M1/M2 states, omits T
      cells and other signaling pathways, and represents vasculature only as a
      source of recruited macrophages and drug penetration.
    readouts:
    - name: Tumor-cell density under optimized combination treatment
      target: Uncontrolled Cell Proliferation
      direction: DECREASED
      interpretation: >-
        Lower simulated tumor-cell density reports suppression of the modeled
        proliferative endpoint under the optimized schedule; it does not establish
        efficacy in people with IDH-wildtype glioblastoma.
      evidence:
      - reference: PMID:40779623
        reference_title: "Multiscale mathematical model-informed reinforcement learning optimizes combination treatment scheduling in glioblastoma evolution."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: "Accordingly, the Fokker-Planck equation–based surrogate model demonstrates that, under the most effective treatment scheduling, the predicted population’s TC density remains at a low level with a high probability (Fig. 8F)."
        explanation: >-
          Reports the direction of the tumor-cell-density output under the
          reinforcement-learning-selected combination schedule.
    evidence:
    - reference: PMID:40779623
      reference_title: "Multiscale mathematical model-informed reinforcement learning optimizes combination treatment scheduling in glioblastoma evolution."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "We first develop a multiscale agent-based model (MSABM) for a critical biological scenario where interactions between tumor-associated macrophages (TAMs) and tumor cells (TCs) underlie immunotherapy resistance in glioblastoma."
      explanation: >-
        Establishes that tumor-cell and macrophage interactions are explicitly
        represented in the glioblastoma agent-based model.
  variables:
  - name: Tumor-cell density
    dataset_identifier: c_T
    description: Normalized tumor-cell population state used by the surrogate and reinforcement-learning environment.
    unit: normalized density
    mappings_list:
    - preferred_term: cell population proliferation
      term:
        id: GO:0008283
        label: cell population proliferation
  - name: Predicted population survival probability
    dataset_identifier: survival_probability
    description: Population-level state and optimization outcome derived from modeled tumor-cell density.
    unit: probability
  findings:
  - statement: >-
      The selected four-week-interval policy combined continuous CSF1R inhibition
      ending after week 20 with continuous IGF1R inhibition beginning at week 5.
    evidence:
    - reference: PMID:40779623
      reference_title: "Multiscale mathematical model-informed reinforcement learning optimizes combination treatment scheduling in glioblastoma evolution."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "By the above procedures, we identified the optimal treatment involving continuous use of CSF1R_I ending after week 20, combined with continuous use of IGF1R_I starting from week 5."
      explanation: Directly states the reinforcement-learning-selected treatment schedule.
  evidence:
  - reference: PMID:40779623
    reference_title: "Multiscale mathematical model-informed reinforcement learning optimizes combination treatment scheduling in glioblastoma evolution."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Here, we describe a multiscale mathematical model-informed reinforcement learning (M4RL) framework to simulate dynamic tumor-microenvironment interactions and optimize drug combination scheduling."
    explanation: Establishes the composition and optimization purpose of the computational framework.
  notes: >-
    Repository inspected at commit 3f64a2cbeb6797cd281c19d70a838282996f62b2.
    The three core multiscale agent-based targets compiled after explicitly
    selecting C++11, and all four Python scripts passed syntax compilation. The
    spatial-transcriptomic C++ target did not compile because OpenMP was not
    declared, and no dependency manifest or license file was present.
treatments:
- name: Maximal Safe Resection
  description: >-
    Aggressive surgical resection aims to maximize extent of resection while
    preserving neurological function. Greater extent of resection correlates with
    improved survival. Fluorescence-guided surgery with 5-ALA improves resection.
  treatment_term:
    preferred_term: Gross Total Resection
    term:
      id: NCIT:C131672
      label: Gross Total Resection
- name: Radiation Therapy
  description: >-
    External beam radiation therapy (60 Gy in 30 fractions) is standard adjuvant
    treatment. Hypofractionated regimens may be used in elderly or poor performance
    status patients.
  therapeutic_modality: RADIOTHERAPY
  treatment_term:
    preferred_term: Radiation Therapy
    term:
      id: NCIT:C15313
      label: Radiation Therapy
- name: Temozolomide Chemotherapy
  description: >-
    Concurrent and adjuvant temozolomide (Stupp protocol) is standard of care.
    Temozolomide is an oral alkylating agent that crosses the blood-brain barrier.
    Benefit is greatest in MGMT methylated tumors.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
    therapeutic_agent:
    - preferred_term: temozolomide
      term:
        id: NCIT:C1244
        label: Temozolomide
  evidence:
  - reference: NCIT:C1244
    reference_title: "\"Temozolomide (NCIT)\""
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Temozolomide | Accepted_Therapeutic_Use_For | - | - | Malignant glioma (Anaplastic astrocytoma; Anaplastic oligodendrogliomas; Anaplastic oligoastrocytomas; Glioblastoma multiforme); Metastatic melanoma"
    explanation: >-
      NCI Thesaurus asserts accepted therapeutic use of temozolomide for
      malignant glioma, including glioblastoma multiforme.
- name: Tumor Treating Fields (TTFields)
  description: >-
    Alternating electric fields delivered via scalp arrays disrupt tumor cell
    mitosis. Added to maintenance temozolomide, TTFields extend median survival
    by approximately 5 months in newly diagnosed glioblastoma.
  treatment_term:
    preferred_term: cranial electrical stimulation
    term:
      id: NCIT:C116561
      label: Cranial Electrical Stimulation
- name: Bevacizumab
  description: >-
    Anti-VEGF monoclonal antibody used for recurrent glioblastoma. Reduces
    peritumoral edema and steroid requirements but does not clearly extend
    overall survival. FDA approved for recurrent disease.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: bevacizumab
      term:
        id: NCIT:C2039
        label: Bevacizumab
disease_term:
  preferred_term: IDH-wildtype glioblastoma
  term:
    id: MONDO:0850335
    label: IDH-wildtype glioblastoma

classifications:
  icdo_morphology:
    classification_value: Glioma
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
references:
- reference: DOI:10.1007/s00401-023-02654-1
  title: “De novo replication repair deficient glioblastoma, IDH-wildtype” is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments.
    supporting_text: Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments.
    evidence:
    - reference: DOI:10.1007/s00401-023-02654-1
      reference_title: “De novo replication repair deficient glioblastoma, IDH-wildtype” is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments.
      explanation: Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
- reference: DOI:10.1007/s00432-025-06171-4
  title: 'Limited survival benefit in patients diagnosed with glioblastoma post-2016: a SEER population based registry analysis'
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: 'Limited survival benefit in patients diagnosed with glioblastoma post-2016: a SEER population based registry analysis'
    supporting_text: 'Limited survival benefit in patients diagnosed with glioblastoma post-2016: a SEER population based registry analysis'
- reference: DOI:10.1007/s10014-022-00446-1
  title: 'Update of the 2021 WHO classification of tumors of the central nervous system: adult diffuse gliomas'
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: 'Update of the 2021 WHO classification of tumors of the central nervous system: adult diffuse gliomas'
    supporting_text: 'Update of the 2021 WHO classification of tumors of the central nervous system: adult diffuse gliomas'
- reference: DOI:10.1007/s11060-024-04682-7
  title: Global post‑marketing safety surveillance of Tumor Treating Fields (TTFields) therapy in over 25,000 patients with CNS malignancies treated between 2011–2022
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: Tumor Treating Fields (TTFields) are alternating electric fields that disrupt cancer cell processes.
    supporting_text: Tumor Treating Fields (TTFields) are alternating electric fields that disrupt cancer cell processes.
    evidence:
    - reference: DOI:10.1007/s11060-024-04682-7
      reference_title: Global post‑marketing safety surveillance of Tumor Treating Fields (TTFields) therapy in over 25,000 patients with CNS malignancies treated between 2011–2022
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Tumor Treating Fields (TTFields) are alternating electric fields that disrupt cancer cell processes.
      explanation: Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
- reference: DOI:10.1007/s11060-024-04808-x
  title: 'Glioblastoma in the real-world setting: patterns of care and outcome in the Austrian population'
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: We present results of a retrospective population-based investigation of patterns of care and outcome of glioblastoma patients in Austria.
    supporting_text: We present results of a retrospective population-based investigation of patterns of care and outcome of glioblastoma patients in Austria.
    evidence:
    - reference: DOI:10.1007/s11060-024-04808-x
      reference_title: 'Glioblastoma in the real-world setting: patterns of care and outcome in the Austrian population'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We present results of a retrospective population-based investigation of patterns of care and outcome of glioblastoma patients in Austria.
      explanation: Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
- reference: DOI:10.1007/s11060-025-04946-w
  title: Long-term survival, patterns of progression, and patterns of use for patients with newly diagnosed glioblastoma treated with or without Tumor Treating Fields (TTFields) in a real-world setting
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: Long-term survival, patterns of progression, and patterns of use for patients with newly diagnosed glioblastoma treated with or without Tumor Treating Fields (TTFields) in a real-world setting
    supporting_text: Long-term survival, patterns of progression, and patterns of use for patients with newly diagnosed glioblastoma treated with or without Tumor Treating Fields (TTFields) in a real-world setting
- reference: DOI:10.1016/j.esmoop.2024.102943
  title: 'REGOMA-OSS: a large, Italian, multicenter, prospective, observational study evaluating the efficacy and safety of regorafenib in patients with recurrent glioblastoma'
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: 'REGOMA-OSS: a large, Italian, multicenter, prospective, observational study evaluating the efficacy and safety of regorafenib in patients with recurrent glioblastoma'
    supporting_text: 'REGOMA-OSS: a large, Italian, multicenter, prospective, observational study evaluating the efficacy and safety of regorafenib in patients with recurrent glioblastoma'
- reference: DOI:10.1038/s41467-024-51315-8
  title: A real-world observation of patients with glioblastoma treated with a personalized peptide vaccine
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: A real-world observation of patients with glioblastoma treated with a personalized peptide vaccine
    supporting_text: A real-world observation of patients with glioblastoma treated with a personalized peptide vaccine
- reference: DOI:10.1038/s41467-024-52167-y
  title: Glioblastoma cells increase expression of notch signaling and synaptic genes within infiltrated brain tissue
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: Glioblastoma cells increase expression of notch signaling and synaptic genes within infiltrated brain tissue
    supporting_text: Glioblastoma cells increase expression of notch signaling and synaptic genes within infiltrated brain tissue
- reference: DOI:10.1038/s41591-024-02969-w
  title: A prognostic neural epigenetic signature in high-grade glioma
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: Neural–tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is limited.
    supporting_text: Neural–tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is limited.
    evidence:
    - reference: DOI:10.1038/s41591-024-02969-w
      reference_title: A prognostic neural epigenetic signature in high-grade glioma
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Neural–tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is limited.
      explanation: Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
- reference: DOI:10.1093/neuonc/noad100
  title: Molecular diagnostic tools for the World Health Organization (WHO) 2021 classification of gliomas, glioneuronal and neuronal tumors; an EANO guideline
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: In the 5th edition of the WHO CNS tumor classification (CNS5, 2021), multiple molecular characteristics became essential diagnostic criteria for many additional CNS tumor types.
    supporting_text: In the 5th edition of the WHO CNS tumor classification (CNS5, 2021), multiple molecular characteristics became essential diagnostic criteria for many additional CNS tumor types.
    evidence:
    - reference: DOI:10.1093/neuonc/noad100
      reference_title: Molecular diagnostic tools for the World Health Organization (WHO) 2021 classification of gliomas, glioneuronal and neuronal tumors; an EANO guideline
      supports: SUPPORT
      evidence_source: OTHER
      snippet: In the 5th edition of the WHO CNS tumor classification (CNS5, 2021), multiple molecular characteristics became essential diagnostic criteria for many additional CNS tumor types.
      explanation: Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
- reference: DOI:10.1093/neuonc/noae085
  title: Immunotherapy drives mesenchymal tumor cell state shift and TME immune response in glioblastoma patients
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: Glioblastoma is a highly aggressive type of brain tumor for which there is no curative treatment available.
    supporting_text: Glioblastoma is a highly aggressive type of brain tumor for which there is no curative treatment available.
    evidence:
    - reference: DOI:10.1093/neuonc/noae085
      reference_title: Immunotherapy drives mesenchymal tumor cell state shift and TME immune response in glioblastoma patients
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Glioblastoma is a highly aggressive type of brain tumor for which there is no curative treatment available.
      explanation: Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
- reference: DOI:10.1093/nop/npae036
  title: Do presenting symptoms predict treatment decisions and survival in glioblastoma? Real-world data from 1458 patients in the Swedish brain tumor registry
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: Glioblastoma is the most common malignant brain tumor in adults.
    supporting_text: Glioblastoma is the most common malignant brain tumor in adults.
    evidence:
    - reference: DOI:10.1093/nop/npae036
      reference_title: Do presenting symptoms predict treatment decisions and survival in glioblastoma? Real-world data from 1458 patients in the Swedish brain tumor registry
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Glioblastoma is the most common malignant brain tumor in adults.
      explanation: Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
- reference: DOI:10.1093/oncolo/oyae227
  title: Recent advances in Tumor Treating Fields (TTFields) therapy for glioblastoma
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: Tumor Treating Fields (TTFields) therapy is a locoregional, anticancer treatment consisting of a noninvasive, portable device that delivers alternating electric fields to tumors through arrays placed on the skin.
    supporting_text: Tumor Treating Fields (TTFields) therapy is a locoregional, anticancer treatment consisting of a noninvasive, portable device that delivers alternating electric fields to tumors through arrays placed on the skin.
    evidence:
    - reference: DOI:10.1093/oncolo/oyae227
      reference_title: Recent advances in Tumor Treating Fields (TTFields) therapy for glioblastoma
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Tumor Treating Fields (TTFields) therapy is a locoregional, anticancer treatment consisting of a noninvasive, portable device that delivers alternating electric fields to tumors through arrays placed on the skin.
      explanation: Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
- reference: DOI:10.1101/2025.01.16.25320661
  title: Whole genome sequencing-based analysis of genetic predisposition to adult glioblastoma
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: Glioblastoma is most commonly reported in the second (pediatric form) and seventh (adult form) decade of life.
    supporting_text: Glioblastoma is most commonly reported in the second (pediatric form) and seventh (adult form) decade of life.
    evidence:
    - reference: DOI:10.1101/2025.01.16.25320661
      reference_title: Whole genome sequencing-based analysis of genetic predisposition to adult glioblastoma
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Glioblastoma is most commonly reported in the second (pediatric form) and seventh (adult form) decade of life.
      explanation: Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
- reference: DOI:10.1126/science.abm5214
  title: Distinct myeloid-derived suppressor cell populations in human glioblastoma
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: The role of glioma-associated myeloid cells in tumor growth and immune evasion remains poorly understood.
    supporting_text: The role of glioma-associated myeloid cells in tumor growth and immune evasion remains poorly understood.
    evidence:
    - reference: DOI:10.1126/science.abm5214
      reference_title: Distinct myeloid-derived suppressor cell populations in human glioblastoma
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The role of glioma-associated myeloid cells in tumor growth and immune evasion remains poorly understood.
      explanation: Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
- reference: DOI:10.11588/heidok.00035474
  title: Tumor Pseudolineages from a Healthy Lineage Template Reveal Organizational Principles and Cell-Fate Modulators in Glioblastoma
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: Tumor Pseudolineages from a Healthy Lineage Template Reveal Organizational Principles and Cell-Fate Modulators in Glioblastoma
    supporting_text: Tumor Pseudolineages from a Healthy Lineage Template Reveal Organizational Principles and Cell-Fate Modulators in Glioblastoma
- reference: DOI:10.1186/s40478-024-01762-7
  title: 'Pediatric-type high-grade gliomas with PDGFRA amplification in adult patients with Li-Fraumeni syndrome: clinical and molecular characterization of three cases'
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: Li-Fraumeni syndrome (LFS) is an autosomal dominant tumor predisposition syndrome caused by heterozygous germline mutations or deletions in the TP53 tumor suppressor gene.
    supporting_text: Li-Fraumeni syndrome (LFS) is an autosomal dominant tumor predisposition syndrome caused by heterozygous germline mutations or deletions in the TP53 tumor suppressor gene.
    evidence:
    - reference: DOI:10.1186/s40478-024-01762-7
      reference_title: 'Pediatric-type high-grade gliomas with PDGFRA amplification in adult patients with Li-Fraumeni syndrome: clinical and molecular characterization of three cases'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Li-Fraumeni syndrome (LFS) is an autosomal dominant tumor predisposition syndrome caused by heterozygous germline mutations or deletions in the TP53 tumor suppressor gene.
      explanation: Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
- reference: DOI:10.17879/freeneuropathology-2024-5892
  title: Adult glioblastoma with Lynch syndrome-associated mismatch repair deficiency forms a distinct high-risk molecular subgroup
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: Glioblastoma is the most frequent and malignant primary brain tumor.
    supporting_text: Glioblastoma is the most frequent and malignant primary brain tumor.
    evidence:
    - reference: DOI:10.17879/freeneuropathology-2024-5892
      reference_title: Adult glioblastoma with Lynch syndrome-associated mismatch repair deficiency forms a distinct high-risk molecular subgroup
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Glioblastoma is the most frequent and malignant primary brain tumor.
      explanation: Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
- reference: DOI:10.32074/1591-951x-823
  title: Adult type diffuse gliomas in the new 2021 WHO Classification
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: Adult type diffuse gliomas in the new 2021 WHO Classification
    supporting_text: Adult type diffuse gliomas in the new 2021 WHO Classification
- reference: DOI:10.3389/fonc.2023.1200815
  title: 'Histological and molecular glioblastoma, IDH-wildtype: a real-world landscape using the 2021 WHO classification of central nervous system tumors'
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: 'Glioblastoma (GBM), the most lethal primary brain malignancy, is divided into histological (hist-GBM) and molecular (mol-GBM) subtypes according to the 2021 World Health Organization classification of central nervous system tumors.'
    supporting_text: Glioblastoma (GBM), the most lethal primary brain malignancy, is divided into histological (hist-GBM) and molecular (mol-GBM) subtypes according to the 2021 World Health Organization classification of central nervous system tumors.
    evidence:
    - reference: DOI:10.3389/fonc.2023.1200815
      reference_title: 'Histological and molecular glioblastoma, IDH-wildtype: a real-world landscape using the 2021 WHO classification of central nervous system tumors'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Glioblastoma (GBM), the most lethal primary brain malignancy, is divided into histological (hist-GBM) and molecular (mol-GBM) subtypes according to the 2021 World Health Organization classification of central nervous system tumors.
      explanation: Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
- reference: DOI:10.3390/biomedicines12061349
  title: 'The 2021 World Health Organization Central Nervous System Tumor Classification: The Spectrum of Diffuse Gliomas'
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: The 2021 edition of the World Health Organization (WHO) classification of central nervous system tumors introduces significant revisions across various tumor types.
    supporting_text: The 2021 edition of the World Health Organization (WHO) classification of central nervous system tumors introduces significant revisions across various tumor types.
    evidence:
    - reference: DOI:10.3390/biomedicines12061349
      reference_title: 'The 2021 World Health Organization Central Nervous System Tumor Classification: The Spectrum of Diffuse Gliomas'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The 2021 edition of the World Health Organization (WHO) classification of central nervous system tumors introduces significant revisions across various tumor types.
      explanation: Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
- reference: DOI:10.3390/cancers17010046
  title: 'Regorafenib Treatment for Recurrent Glioblastoma Beyond Bevacizumab-Based Therapy: A Large, Multicenter, Real-Life Study'
  found_in:
  - Glioblastoma_IDH_Wildtype-deep-research-falcon.md
  findings:
  - statement: In the REGOMA trial, regorafenib demonstrated an overall survival advantage over lomustine, and it has become a recommended treatment for recurrent glioblastoma in guidelines.
    supporting_text: In the REGOMA trial, regorafenib demonstrated an overall survival advantage over lomustine, and it has become a recommended treatment for recurrent glioblastoma in guidelines.
    evidence:
    - reference: DOI:10.3390/cancers17010046
      reference_title: 'Regorafenib Treatment for Recurrent Glioblastoma Beyond Bevacizumab-Based Therapy: A Large, Multicenter, Real-Life Study'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In the REGOMA trial, regorafenib demonstrated an overall survival advantage over lomustine, and it has become a recommended treatment for recurrent glioblastoma in guidelines.
      explanation: Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
📚

References & Deep Research

References

23
DOI:10.1007/s00401-023-02654-1
“De novo replication repair deficient glioblastoma, IDH-wildtype” is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade
1 finding
Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments.
"Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments."
Show evidence (1 reference)
DOI:10.1007/s00401-023-02654-1 SUPPORT Human Clinical
"Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments."
Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
DOI:10.1007/s00432-025-06171-4
Limited survival benefit in patients diagnosed with glioblastoma post-2016: a SEER population based registry analysis
1 finding
Limited survival benefit in patients diagnosed with glioblastoma post-2016: a SEER population based registry analysis
"Limited survival benefit in patients diagnosed with glioblastoma post-2016: a SEER population based registry analysis"
DOI:10.1007/s10014-022-00446-1
Update of the 2021 WHO classification of tumors of the central nervous system: adult diffuse gliomas
1 finding
Update of the 2021 WHO classification of tumors of the central nervous system: adult diffuse gliomas
"Update of the 2021 WHO classification of tumors of the central nervous system: adult diffuse gliomas"
DOI:10.1007/s11060-024-04682-7
Global post‑marketing safety surveillance of Tumor Treating Fields (TTFields) therapy in over 25,000 patients with CNS malignancies treated between 2011–2022
1 finding
Tumor Treating Fields (TTFields) are alternating electric fields that disrupt cancer cell processes.
"Tumor Treating Fields (TTFields) are alternating electric fields that disrupt cancer cell processes."
Show evidence (1 reference)
DOI:10.1007/s11060-024-04682-7 SUPPORT Human Clinical
"Tumor Treating Fields (TTFields) are alternating electric fields that disrupt cancer cell processes."
Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
DOI:10.1007/s11060-024-04808-x
Glioblastoma in the real-world setting: patterns of care and outcome in the Austrian population
1 finding
We present results of a retrospective population-based investigation of patterns of care and outcome of glioblastoma patients in Austria.
"We present results of a retrospective population-based investigation of patterns of care and outcome of glioblastoma patients in Austria."
Show evidence (1 reference)
DOI:10.1007/s11060-024-04808-x SUPPORT Human Clinical
"We present results of a retrospective population-based investigation of patterns of care and outcome of glioblastoma patients in Austria."
Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
DOI:10.1007/s11060-025-04946-w
Long-term survival, patterns of progression, and patterns of use for patients with newly diagnosed glioblastoma treated with or without Tumor Treating Fields (TTFields) in a real-world setting
1 finding
Long-term survival, patterns of progression, and patterns of use for patients with newly diagnosed glioblastoma treated with or without Tumor Treating Fields (TTFields) in a real-world setting
"Long-term survival, patterns of progression, and patterns of use for patients with newly diagnosed glioblastoma treated with or without Tumor Treating Fields (TTFields) in a real-world setting"
DOI:10.1016/j.esmoop.2024.102943
REGOMA-OSS: a large, Italian, multicenter, prospective, observational study evaluating the efficacy and safety of regorafenib in patients with recurrent glioblastoma
1 finding
REGOMA-OSS: a large, Italian, multicenter, prospective, observational study evaluating the efficacy and safety of regorafenib in patients with recurrent glioblastoma
"REGOMA-OSS: a large, Italian, multicenter, prospective, observational study evaluating the efficacy and safety of regorafenib in patients with recurrent glioblastoma"
DOI:10.1038/s41467-024-51315-8
A real-world observation of patients with glioblastoma treated with a personalized peptide vaccine
1 finding
A real-world observation of patients with glioblastoma treated with a personalized peptide vaccine
"A real-world observation of patients with glioblastoma treated with a personalized peptide vaccine"
DOI:10.1038/s41467-024-52167-y
Glioblastoma cells increase expression of notch signaling and synaptic genes within infiltrated brain tissue
1 finding
Glioblastoma cells increase expression of notch signaling and synaptic genes within infiltrated brain tissue
"Glioblastoma cells increase expression of notch signaling and synaptic genes within infiltrated brain tissue"
DOI:10.1038/s41591-024-02969-w
A prognostic neural epigenetic signature in high-grade glioma
1 finding
Neural–tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is limited.
"Neural–tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is limited."
Show evidence (1 reference)
DOI:10.1038/s41591-024-02969-w SUPPORT Human Clinical
"Neural–tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is limited."
Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
DOI:10.1093/neuonc/noad100
Molecular diagnostic tools for the World Health Organization (WHO) 2021 classification of gliomas, glioneuronal and neuronal tumors; an EANO guideline
1 finding
In the 5th edition of the WHO CNS tumor classification (CNS5, 2021), multiple molecular characteristics became essential diagnostic criteria for many additional CNS tumor types.
"In the 5th edition of the WHO CNS tumor classification (CNS5, 2021), multiple molecular characteristics became essential diagnostic criteria for many additional CNS tumor types."
Show evidence (1 reference)
DOI:10.1093/neuonc/noad100 SUPPORT Other
"In the 5th edition of the WHO CNS tumor classification (CNS5, 2021), multiple molecular characteristics became essential diagnostic criteria for many additional CNS tumor types."
Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
DOI:10.1093/neuonc/noae085
Immunotherapy drives mesenchymal tumor cell state shift and TME immune response in glioblastoma patients
1 finding
Glioblastoma is a highly aggressive type of brain tumor for which there is no curative treatment available.
"Glioblastoma is a highly aggressive type of brain tumor for which there is no curative treatment available."
Show evidence (1 reference)
DOI:10.1093/neuonc/noae085 SUPPORT Human Clinical
"Glioblastoma is a highly aggressive type of brain tumor for which there is no curative treatment available."
Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
DOI:10.1093/nop/npae036
Do presenting symptoms predict treatment decisions and survival in glioblastoma? Real-world data from 1458 patients in the Swedish brain tumor registry
1 finding
Glioblastoma is the most common malignant brain tumor in adults.
"Glioblastoma is the most common malignant brain tumor in adults."
Show evidence (1 reference)
DOI:10.1093/nop/npae036 SUPPORT Human Clinical
"Glioblastoma is the most common malignant brain tumor in adults."
Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
DOI:10.1093/oncolo/oyae227
Recent advances in Tumor Treating Fields (TTFields) therapy for glioblastoma
1 finding
Tumor Treating Fields (TTFields) therapy is a locoregional, anticancer treatment consisting of a noninvasive, portable device that delivers alternating electric fields to tumors through arrays placed on the skin.
"Tumor Treating Fields (TTFields) therapy is a locoregional, anticancer treatment consisting of a noninvasive, portable device that delivers alternating electric fields to tumors through arrays placed on the skin."
Show evidence (1 reference)
DOI:10.1093/oncolo/oyae227 SUPPORT Human Clinical
"Tumor Treating Fields (TTFields) therapy is a locoregional, anticancer treatment consisting of a noninvasive, portable device that delivers alternating electric fields to tumors through arrays placed on the skin."
Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
DOI:10.1101/2025.01.16.25320661
Whole genome sequencing-based analysis of genetic predisposition to adult glioblastoma
1 finding
Glioblastoma is most commonly reported in the second (pediatric form) and seventh (adult form) decade of life.
"Glioblastoma is most commonly reported in the second (pediatric form) and seventh (adult form) decade of life."
Show evidence (1 reference)
DOI:10.1101/2025.01.16.25320661 Preprint · not peer-reviewed SUPPORT Human Clinical
"Glioblastoma is most commonly reported in the second (pediatric form) and seventh (adult form) decade of life."
Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
DOI:10.1126/science.abm5214
Distinct myeloid-derived suppressor cell populations in human glioblastoma
1 finding
The role of glioma-associated myeloid cells in tumor growth and immune evasion remains poorly understood.
"The role of glioma-associated myeloid cells in tumor growth and immune evasion remains poorly understood."
Show evidence (1 reference)
DOI:10.1126/science.abm5214 SUPPORT Human Clinical
"The role of glioma-associated myeloid cells in tumor growth and immune evasion remains poorly understood."
Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
DOI:10.11588/heidok.00035474
Tumor Pseudolineages from a Healthy Lineage Template Reveal Organizational Principles and Cell-Fate Modulators in Glioblastoma
1 finding
Tumor Pseudolineages from a Healthy Lineage Template Reveal Organizational Principles and Cell-Fate Modulators in Glioblastoma
"Tumor Pseudolineages from a Healthy Lineage Template Reveal Organizational Principles and Cell-Fate Modulators in Glioblastoma"
DOI:10.1186/s40478-024-01762-7
Pediatric-type high-grade gliomas with PDGFRA amplification in adult patients with Li-Fraumeni syndrome: clinical and molecular characterization of three cases
1 finding
Li-Fraumeni syndrome (LFS) is an autosomal dominant tumor predisposition syndrome caused by heterozygous germline mutations or deletions in the TP53 tumor suppressor gene.
"Li-Fraumeni syndrome (LFS) is an autosomal dominant tumor predisposition syndrome caused by heterozygous germline mutations or deletions in the TP53 tumor suppressor gene."
Show evidence (1 reference)
DOI:10.1186/s40478-024-01762-7 SUPPORT Human Clinical
"Li-Fraumeni syndrome (LFS) is an autosomal dominant tumor predisposition syndrome caused by heterozygous germline mutations or deletions in the TP53 tumor suppressor gene."
Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
DOI:10.17879/freeneuropathology-2024-5892
Adult glioblastoma with Lynch syndrome-associated mismatch repair deficiency forms a distinct high-risk molecular subgroup
1 finding
Glioblastoma is the most frequent and malignant primary brain tumor.
"Glioblastoma is the most frequent and malignant primary brain tumor."
Show evidence (1 reference)
DOI:10.17879/freeneuropathology-2024-5892 SUPPORT Human Clinical
"Glioblastoma is the most frequent and malignant primary brain tumor."
Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
DOI:10.32074/1591-951x-823
Adult type diffuse gliomas in the new 2021 WHO Classification
1 finding
Adult type diffuse gliomas in the new 2021 WHO Classification
"Adult type diffuse gliomas in the new 2021 WHO Classification"
DOI:10.3389/fonc.2023.1200815
Histological and molecular glioblastoma, IDH-wildtype: a real-world landscape using the 2021 WHO classification of central nervous system tumors
1 finding
Glioblastoma (GBM), the most lethal primary brain malignancy, is divided into histological (hist-GBM) and molecular (mol-GBM) subtypes according to the 2021 World Health Organization classification of central nervous system tumors.
"Glioblastoma (GBM), the most lethal primary brain malignancy, is divided into histological (hist-GBM) and molecular (mol-GBM) subtypes according to the 2021 World Health Organization classification of central nervous system tumors."
Show evidence (1 reference)
DOI:10.3389/fonc.2023.1200815 SUPPORT Human Clinical
"Glioblastoma (GBM), the most lethal primary brain malignancy, is divided into histological (hist-GBM) and molecular (mol-GBM) subtypes according to the 2021 World Health Organization classification of central nervous system tumors."
Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
DOI:10.3390/biomedicines12061349
The 2021 World Health Organization Central Nervous System Tumor Classification: The Spectrum of Diffuse Gliomas
1 finding
The 2021 edition of the World Health Organization (WHO) classification of central nervous system tumors introduces significant revisions across various tumor types.
"The 2021 edition of the World Health Organization (WHO) classification of central nervous system tumors introduces significant revisions across various tumor types."
Show evidence (1 reference)
DOI:10.3390/biomedicines12061349 SUPPORT Human Clinical
"The 2021 edition of the World Health Organization (WHO) classification of central nervous system tumors introduces significant revisions across various tumor types."
Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.
DOI:10.3390/cancers17010046
Regorafenib Treatment for Recurrent Glioblastoma Beyond Bevacizumab-Based Therapy: A Large, Multicenter, Real-Life Study
1 finding
In the REGOMA trial, regorafenib demonstrated an overall survival advantage over lomustine, and it has become a recommended treatment for recurrent glioblastoma in guidelines.
"In the REGOMA trial, regorafenib demonstrated an overall survival advantage over lomustine, and it has become a recommended treatment for recurrent glioblastoma in guidelines."
Show evidence (1 reference)
DOI:10.3390/cancers17010046 SUPPORT Human Clinical
"In the REGOMA trial, regorafenib demonstrated an overall survival advantage over lomustine, and it has become a recommended treatment for recurrent glioblastoma in guidelines."
Deep research cited this publication as relevant literature for Glioblastoma IDH Wildtype.

Deep Research

2
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Disease Characteristics Research Template
Edison Scientific Literature 63 citations 2026-04-05T15:38:21.554197

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Glioblastoma, IDH-Wildtype
  • MONDO ID: (if available)
  • Category:

Research Objectives

Please provide a comprehensive research report on Glioblastoma, IDH-Wildtype covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
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  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
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  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
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15. Model Organisms

  • Model Types:
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  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
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  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
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  • Resources:
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Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Glioblastoma, IDH‑wildtype — Disease Characteristics Research Report (2026-04-05)

Target disease

  • Disease name: Glioblastoma, IDH‑wildtype (adult-type diffuse glioma)
  • MONDO ID: MONDO:0018177 (glioblastoma) (antonelli2022adulttypediffuse media 491d0085)
  • Category: Primary malignant CNS tumor; adult-type diffuse glioma; CNS WHO grade 4 by definition (gue2024the2021world pages 9-12, antonelli2022adulttypediffuse pages 10-11)

Executive summary

Glioblastoma, IDH‑wildtype (GBM-IDHwt) is the most common adult grade 4 diffuse astrocytic tumor and is defined in WHO CNS5 (2021) by IDH-wildtype status plus either classic grade-4 histology (necrosis and/or microvascular proliferation) or one of three molecular “grade-4” signatures (TERT promoter mutation, EGFR amplification, combined whole-chromosome +7/−10) even when histology appears lower grade. (guo2023histologicalandmolecular pages 1-2, antonelli2022adulttypediffuse pages 10-11, antonelli2022adulttypediffuse media 491d0085)

In recent, large real-world cohorts explicitly restricted to pathologically verified IDH‑wildtype GBM, median survival is ~11–12 months with ~21–26% 2-year survival. (bruhn2024dopresentingsymptoms pages 1-2, hainfellner2024glioblastomainthe pages 1-3, dhingra2025limitedsurvivalbenefit pages 1-2)

1. Disease information

1.1. What is the disease?

Glioblastoma, IDH‑wildtype is an infiltrative diffuse astrocytic glioma lacking IDH mutation (and typically lacking histone H3 alterations) with WHO grade 4 biology. It is diagnosed either by grade-4 histology (necrosis and/or microvascular proliferation) or by specific molecular features that are sufficient to assign grade 4 in IDH‑wildtype diffuse astrocytic tumors. (antonelli2022adulttypediffuse pages 10-11, antonelli2022adulttypediffuse media 491d0085)

Direct abstract-level quote supporting definition: In a real-world WHO CNS5 reclassification study, “IDH-wildtype diffuse astrocytic tumors without the histological features of GBM… are considered as molecular GBM (mol-GBM, WHO grade 4) if they harbor any of the following molecular abnormalities: TERT promoter mutation, EGFR amplification, or chromosomal + 7/−10 copy changes.” (guo2023histologicalandmolecular pages 1-2)

1.2. Key identifiers and ontologies

  • MONDO: glioblastoma MONDO:0018177 (antonelli2022adulttypediffuse media 491d0085)
  • EFO: glioblastoma multiforme EFO:0000519 (Open Targets mapping shown in tool output) (antonelli2022adulttypediffuse media 491d0085)
  • MeSH / ICD-10/ICD-11 / Orphanet / OMIM: Not reliably retrievable from the currently ingested sources in this run; these should be added from curated terminologies in a subsequent pass.

1.3. Common synonyms / alternative names

  • Glioblastoma, GBM; glioblastoma multiforme (legacy term)
  • “Molecular glioblastoma” / “mol‑GBM” (IDH‑wildtype diffuse astrocytic tumor that meets molecular grade-4 criteria without classic histology) (guo2023histologicalandmolecular pages 1-2, antonelli2022adulttypediffuse pages 10-11)

1.4. Evidence sources used in this report

This report primarily uses aggregated disease-level resources: WHO CNS5-oriented reviews and guidelines, plus population/registry real‑world cohorts (e.g., Swedish Brain Tumor Registry; Austrian national registry; SEER) and selected clinical trial/observational studies. (bruhn2024dopresentingsymptoms pages 1-2, hainfellner2024glioblastomainthe pages 1-3, dhingra2025limitedsurvivalbenefit pages 1-2)

2. Etiology

2.1. Disease causal factors (mechanistic/genetic)

GBM-IDHwt is driven by recurrent alterations in signaling and cell-cycle networks (RTK/RAS/PI3K; TP53; RB pathways), and is defined diagnostically by a subset of molecular hallmarks (TERT promoter mutation, EGFR amplification, and/or +7/−10). (antonelli2022adulttypediffuse pages 10-11, guo2023histologicalandmolecular pages 1-2)

2.2. Genetic risk factors / predisposition

Mismatch repair (MMR) deficiency and Lynch-associated glioblastoma subgroups

Recent data highlight a rare but clinically important subset of adult IDH‑wildtype glioblastomas with mismatch-repair deficiency and hypermutation: - In a prospective genomic profiling series of 459 primary treatment-naïve adult IDH‑wildtype GBMs, a distinct “de novo replication repair deficient” subgroup comprised 2% (9/459), defined by somatic hypermutation and biallelic inactivation of a canonical MMR gene; deleterious MMR variants were often present in the germline (heterozygous) with somatic second hit, consistent with underlying Lynch syndrome. This subgroup had universal giant cell histology and lacked canonical EGFR amplification and +7/−10; median OS was 36.8 vs 15.5 months for other GBMs (p<0.001), and 4/5 patients treated with immune checkpoint blockade survived >3 years. (hadad2024“denovoreplication pages 1-2) - A separate study (n=218) described a rare germline MMR/Lynch subgroup (G3/MMR) with very poor median survival (3.25 months post-surgery) in five germline MMR-variant carriers (MLH1, PMS2, MSH2, MSH6). (georgescu2024adultglioblastomawith pages 1-2)

These studies collectively support a clinically actionable concept: a minority of GBM-IDHwt arises in the context of hereditary (or constitutional) MMR deficiency, often with hypermutation, and may have differential prognosis and potential sensitivity to checkpoint blockade. (hadad2024“denovoreplication pages 1-2, georgescu2024adultglioblastomawith pages 1-2)

Germline predisposition prevalence estimates (WGS-based)

A WGS-based germline analysis in an unselected cohort of 98 adult WHO grade 4 glioma patients (93.9% IDH‑wildtype) reported: - Pathogenic/likely pathogenic germline variants relevant to glioblastoma in ~11% of patients. (opijnen2025wholegenomesequencingbased pages 1-6) - Enrichment for MMR genes (e.g., MSH6, PMS2, MSH2) and other predisposition genes including TP53 (Li‑Fraumeni), NF1, BRCA1, SUFU. (opijnen2025wholegenomesequencingbased pages 1-6) - MMR deficiency as a major mechanism: 7.1% carried an MMR-gene PGV with multiple MSI cases. (opijnen2025wholegenomesequencingbased pages 15-18)

Li-Fraumeni syndrome (TP53) and adult high-grade gliomas

In three adult Li‑Fraumeni syndrome patients with high-grade gliomas, tumors were IDH1/2-wildtype but lacked typical GBM-IDHwt hallmarks (TERT promoter mutation, EGFR amplification, +7/−10). Instead, they showed PDGFRA amplification and methylation profiles aligning with pediatric-type high-grade glioma RTK1, suggesting that adult predisposition syndromes can yield tumors that mimic glioblastoma histologically but are molecularly distinct. (kibe2024pediatrictypehighgradegliomas pages 1-2)

2.3. Environmental risk factors

Within the ingested evidence for this run, environmental/occupational risk factors were not supported by extractable primary text. The report therefore does not assert specific environmental risk magnitudes.

2.4. Protective factors and gene–environment interactions

Not established in the retrieved evidence set.

3. Phenotypes

3.1. Common presenting symptoms (with frequencies when available)

Swedish Brain Tumor Registry (SBTR), IDH-wildtype only (n=1,458; 2018–2021): presenting symptom categories included focal neurological deficits, cognitive dysfunction, headache, epilepsy (seizures), signs of raised intracranial pressure, and cranial nerve symptoms. Median survival was 345 days (~11.5 months) and 2-year survival 21.5%. (bruhn2024dopresentingsymptoms pages 1-2)

Austrian population registry (n=1,420; 2014–2018; IDH-wildtype known in 78.5%): symptom frequencies at presentation were focal neurological deficits 42.2%, headache 17.3%, epilepsy 15.6%, personality changes 10.9%. (hainfellner2024glioblastomainthe pages 3-4)

3.2. Prognostic impact of key phenotypes

In SBTR, initial cognitive dysfunction was associated with substantially shorter survival (median 265 vs 409 days, P<.001) and remained independently adverse after multivariable adjustment; patients with cognitive deficits were less likely to undergo radical surgery and intensive oncologic therapy. (bruhn2024dopresentingsymptoms pages 1-2)

3.3. Phenotype characteristics

  • Typical onset: predominantly late-adult; in the SBTR IDH-wildtype cohort median age was 66 years (range 18–89). (bruhn2024dopresentingsymptoms pages 1-2)
  • Course/progression: rapidly progressive with high recurrence; infiltrative spread limits complete resection. (harwood2024glioblastomacellsincrease pages 1-2)

3.4. Suggested HPO mappings (examples)

From registry symptom categories and standard neuro-oncology presentation: - Seizures: HP:0001250 - Headache: HP:0002315 - Cognitive impairment: HP:0100543 - Focal neurological deficit / hemiparesis: HP:0001263 (or HP:0001276 for weakness; mapping may be refined by chart abstraction) - Signs of increased intracranial pressure (e.g., nausea/vomiting, papilledema): HP:0002516, HP:0002013

(These HPO mappings are ontology suggestions; the evidence sources provide symptom categories but not term IDs.) (bruhn2024dopresentingsymptoms pages 1-2, hainfellner2024glioblastomainthe pages 3-4)

4. Genetic / molecular information

4.1. Defining diagnostic molecular features (WHO CNS5)

WHO CNS5 defines glioblastoma, IDH‑wildtype as an IDH-wildtype diffuse astrocytic tumor with either (i) necrosis and/or microvascular proliferation, or (ii) one or more of: TERT promoter mutation, EGFR amplification, and/or +7/−10. (antonelli2022adulttypediffuse pages 10-11, antonelli2022adulttypediffuse media 491d0085)

A visual summary of this WHO diagnostic algorithm is available in Figure 2 from Antonelli & Poliani (2022). (antonelli2022adulttypediffuse media 491d0085)

4.2. Common somatic alterations (representative; not exhaustive)

Across real-world WHO CNS5 reclassification cohorts, recurrent alterations include: - EGFR, TERT, CDKN2A/B, PTEN, and copy-number changes across chromosomes including 7 and 10. (guo2023histologicalandmolecular pages 1-2)

Quote (abstract) for a cohort-level molecular summary: “Common molecular features included copy-number changes in chromosomes 1, 7, 9, 10, and 19, as well as alterations in EGFR, TERT, CDKN2A/B, and PTEN…” (guo2023histologicalandmolecular pages 1-2)

4.3. Predictive biomarker: MGMT promoter methylation

MGMT promoter methylation is a key predictive biomarker for temozolomide benefit and is incorporated into molecular-testing guidance for WHO CNS5 gliomas. (sahm2023moleculardiagnostictools pages 14-14, sahm2023moleculardiagnostictools pages 2-3) - Austrian registry: MGMT promoter methylation present in 34.3% of patients (unknown 30.2%). (hainfellner2024glioblastomainthe pages 3-4) - WHO2021 real-world reclassification cohort: MGMT promoter methylation predicted improved survival. (guo2023histologicalandmolecular pages 1-2)

4.4. Open Targets disease–gene associations (selected)

Open Targets lists multiple associated targets for “glioblastoma multiforme” including EGFR, TP53, IDH1, PTEN, ATRX, RB1, NF1, TERT, among others (mapping evidence includes literature PMIDs). (antonelli2022adulttypediffuse media 491d0085)

5. Mechanism / pathophysiology

5.1. Tumor cell states and plasticity (single-cell/spatial)

Spatial transcriptomics in patient samples indicates that transcriptional subtype distinctions (classical/proneural/mesenchymal) are strongest in tumor cores but attenuate in infiltrated brain tissue, consistent with state convergence during invasion. (harwood2024glioblastomacellsincrease pages 1-2)

A key mechanistic theme is cell-state plasticity (e.g., transitions toward a mesenchymal program) and coupling to microenvironmental niches. (hendriksen2024immunotherapydrivesmesenchymal pages 1-3, forster2024tumorpseudolineagesfrom pages 27-30)

5.2. Infiltration and recurrence

GBM cells disperse into adjacent parenchyma, often tracking vasculature and white matter, enabling escape from resection; recurrence is frequent and often local. A spatial-transcriptomics study notes recurrence “within resection margins in ~90% of patients within one year.” (harwood2024glioblastomacellsincrease pages 1-2)

5.3. Neural/synaptic and developmental programs

A 2024 Nature Medicine study defined a prognostic “neural epigenetic signature” across n=1,058 glioblastoma samples; high-neural tumors showed synaptic-gene upregulation and worse outcomes (median OS 14.2 vs 21.2 months, median PFS 6.2 vs 10.0 months). (drexler2024aprognosticneural pages 1-2)

5.4. Immunosuppressive myeloid microenvironment (2024–2025)

A 2025 Science study used single-cell RNA-seq (33 gliomas) and identified distinct MDSC populations in IDH-wildtype glioblastoma, including early progenitor MDSCs (E‑MDSCs) and monocytic MDSCs (M‑MDSCs). Spatial transcriptomics localized E‑MDSCs with metabolic stem-like tumor cells in pseudopalisading regions and suggested reciprocal tumor–myeloid cross-talk (tumor chemokines recruit E‑MDSCs; E‑MDSCs provide tumor-supportive growth factors). (jackson2025distinctmyeloidderivedsuppressor pages 1-3)

5.5. Suggested ontology mappings

GO biological processes (examples): - cell proliferation; cell migration; angiogenesis; hypoxia response; antigen processing and presentation; immune suppression (conceptual mapping based on described programs). (harwood2024glioblastomacellsincrease pages 1-2, jackson2025distinctmyeloidderivedsuppressor pages 1-3)

Cell Ontology (CL) terms (examples): - tumor-associated macrophage / microglia (as described); myeloid-derived suppressor cell (E‑MDSC / M‑MDSC populations) (jackson2025distinctmyeloidderivedsuppressor pages 1-3)

6. Diagnostics

6.1. Integrated histomolecular diagnosis (WHO CNS5) and testing workflows

WHO CNS5 requires integrated histology plus molecular assessment for many CNS tumors. For adult diffuse gliomas, when an IDH‑wildtype diffuse glioma lacks necrosis/microvascular proliferation, it should be tested for EGFR amplification, TERT promoter mutation, and +7/−10 to establish a WHO grade-4 diagnosis. (antonelli2022adulttypediffuse pages 10-11)

6.2. Molecular testing (EANO guideline highlights; 2023)

The EANO guideline on molecular diagnostic tools emphasizes that WHO CNS5 requires an integrated “histomolecular” diagnosis, and explicitly includes MGMT promoter methylation because of its predictive role in IDH‑wildtype GBM. (sahm2023moleculardiagnostictools pages 2-3)

For MGMT promoter methylation testing, EANO recommends reporting assay details (including CpGs interrogated), the numerical test value, and explicit cutoffs/gray zones; it discourages MGMT immunohistochemistry as the basis for clinical decision-making. (sahm2023moleculardiagnostictools pages 14-14)

6.3. MGMT assay-method considerations

Methylation-array platforms can output MGMT promoter information, but the guideline notes that “optimal methods and respective cut-offs… are debated” and that CNV-based inferences should be confirmed by orthogonal methods. (sahm2023moleculardiagnostictools pages 11-12)

7. Outcomes / prognosis

7.1. Registry-derived survival statistics (recent)

  • Sweden (SBTR), IDH‑wildtype only (2018–2021; n=1,458): median survival 345 days and 2-year survival 21.5%. (bruhn2024dopresentingsymptoms pages 1-2)
  • Austria (ABTR-SANOnet; 2014–2018; n=1,420): median OS 11.6 months overall and 10.9 months in proven IDH‑wildtype. (hainfellner2024glioblastomainthe pages 1-3)
  • SEER era analysis (surgery + postoperative RT; n=27,534): median OS 15 months in 2016–2020 vs 14 months in 2005–2015; 24‑month OS ~25.6% (2016–2020). (Note: SEER analysis not IDH‑specific and lacks TTFields usage capture.) (dhingra2025limitedsurvivalbenefit pages 1-2)

7.2. Prognostic factors supported in retrieved sources

  • Baseline cognitive impairment: independently adverse (bruhn2024dopresentingsymptoms pages 1-2)
  • MGMT promoter methylation: favorable/predictive (guo2023histologicalandmolecular pages 1-2, sahm2023moleculardiagnostictools pages 14-14)
  • Maximal resection and Stupp-protocol treatment: favorable (guo2023histologicalandmolecular pages 1-2)

8. Treatment

8.1. Standard of care (real-world and consensus summary)

The treatment backbone remains maximal safe resection followed by radiotherapy with concurrent and adjuvant temozolomide (“Stupp regimen”). (antonelli2022adulttypediffuse pages 10-11, latzer2024arealworldobservation pages 1-2)

Predictive stratifier: temozolomide benefit is greater in MGMT promoter–methylated tumors, and likely marginal in MGMT-unmethylated tumors. (antonelli2022adulttypediffuse pages 10-11, sahm2023moleculardiagnostictools pages 14-14)

Suggested MAXO terms (examples): - Maximal surgical resection: MAXO:0001175 (neurosurgical tumor resection; placeholder mapping) - Radiotherapy: MAXO:0000058 - Alkylating chemotherapy (temozolomide): MAXO:0000647 (chemotherapy; placeholder mapping)

8.2. Tumor Treating Fields (TTFields) — real-world implementation and safety

Safety (post-marketing; 2011–2022): in a global PMS dataset of 25,898 TTFields-treated CNS tumor patients (68% newly diagnosed GBM), TTFields-related AEs occurred in 56%; the most frequent were beneath-array skin reactions (43%), electric sensation/tingling (14%), and warmth (12%). No TTFields-related systemic adverse events were reported. (mrugala2024globalpost‑marketingsafety pages 1-2)

Real-world effectiveness: a single-institution cohort (2015–2023; follow-up through 2024) of 208 newly diagnosed GBM patients showed longer survival with TTFields: median OS 21.7 vs 17.7 months (p=0.029) and PFS 12.4 vs 9.6 months (p=0.047) for TTFields vs no TTFields. (riegel2025longtermsurvivalpatterns pages 1-2)

Suggested MAXO term: TTFields (device-based electrical field therapy): MAXO:0001017 (device therapy; placeholder mapping).

8.3. Regorafenib for recurrent glioblastoma (real-world and evolving evidence)

Prospective observational (REGOMA-OSS; 30 Italian centers; n=190; 92.4% IDH-wildtype): median OS 7.9 months, median PFS 2.6 months; grade 3–4 drug-related AEs 22.6%; dose reductions 36%; no treatment-related deaths. (caccese2024regomaossalarge pages 1-2)

Third-line after bevacizumab (Turkey; n=65; IDH-wildtype): median PFS 2.5 months, median OS 4.1 months; no drug-related deaths reported. (tunbekici2024regorafenibtreatmentfor pages 1-2)

Platform trial update (GBM AGILE; NCT03970447): a reported analysis indicated regorafenib accrual was stopped for futility with mean hazard ratios >1 and low Bayesian probability of benefit across signatures, highlighting uncertainty/heterogeneity in benefit and the need for biomarker-driven selection. (khagi2025recentadvancesin pages 7-8)

Suggested MAXO term: multi-kinase inhibitor therapy: MAXO:0000647 (chemotherapy/targeted therapy; placeholder mapping).

8.4. Immunotherapy/vaccines (2023–2024)

DCVax-L (autologous tumor lysate-loaded dendritic cell vaccine; NCT00045968): in an externally controlled phase 3 study, median OS for newly diagnosed GBM was 19.3 months vs 16.5 months in controls (HR 0.80; P=.002), with 60-month survival 13.0% vs 5.7%; in recurrent GBM, median OS was 13.2 vs 7.8 months (HR 0.58; P<.001). (liau2023…cellvaccination pages 1-2)

Personalized neoantigen peptide vaccine (real-world “individual healing attempt”; n=173; 2015–2023): median OS from first diagnosis 31.9 months (95% CI 25.0–36.5); immune response detected in 90% (87/97) monitored patients; multiple vaccine-induced T-cell responses associated with longer survival (53 vs 27 months, P=0.03). (latzer2024arealworldobservation pages 1-2)

Expert analysis note: Recent literature highlights that glioblastoma immunotherapy outcomes must be interpreted cautiously due to heterogeneous trial designs and immunosuppressive microenvironments, and may require combination strategies targeting myeloid suppression and/or mesenchymal programs. (hendriksen2024immunotherapydrivesmesenchymal pages 1-3, jackson2025distinctmyeloidderivedsuppressor pages 1-3)

9. Prevention

  • Primary prevention: Not established beyond avoidance of unproven risk exposures; the current evidence set does not support actionable population-level prevention recommendations.
  • Secondary prevention / screening: No population screening recommended; surveillance applies mainly to individuals with known hereditary cancer predisposition (e.g., Lynch/MMR deficiency, Li-Fraumeni), but specific imaging surveillance protocols were not extractable from the ingested evidence. (hadad2024“denovoreplication pages 1-2, kibe2024pediatrictypehighgradegliomas pages 1-2)

10. Other species / natural disease

Not addressed in the retrieved evidence set for this run.

11. Model organisms / experimental models

Not comprehensively retrieved in this run. However, mechanistic studies cited here relied on spatial transcriptomics in patients (harwood2024glioblastomacellsincrease pages 1-2), scRNA-seq/spatial in human tumors (jackson2025distinctmyeloidderivedsuppressor pages 1-3), and xenograft modeling noted in neural-signature work (drexler2024aprognosticneural pages 1-2).

Visual evidence

Figure 2 in Antonelli & Poliani (2022) provides a WHO CNS5 diagnostic algorithm showing that GBM-IDHwt can be diagnosed by histologic grade-4 features or by molecular criteria (TERT promoter mutation, EGFR amplification, and/or +7/−10). (antonelli2022adulttypediffuse media 491d0085)

Synthesis table

Category Marker / criterion What it means in glioblastoma, IDH-wildtype Representative frequency / note from provided sources
WHO CNS5 histologic criterion Necrosis and/or microvascular proliferation in an IDH-wildtype diffuse astrocytic glioma Sufficient for diagnosis of glioblastoma, IDH-wildtype, CNS WHO grade 4 when integrated with molecular exclusion of IDH/H3-altered entities (antonelli2022adulttypediffuse pages 10-11, gue2024the2021world pages 9-12, antonelli2022adulttypediffuse media 491d0085) WHO CNS5 defines GBM as IDH-wildtype with either these histologic features or specified molecular features (gue2024the2021world pages 9-12, antonelli2022adulttypediffuse pages 10-11, antonelli2022adulttypediffuse media 491d0085)
WHO CNS5 molecular criterion TERT promoter mutation Can upgrade an otherwise lower-grade appearing IDH-wildtype diffuse astrocytic glioma to molecular glioblastoma; less specific than EGFR amplification or +7/−10 when present alone (guo2023histologicalandmolecular pages 1-2, antonelli2022adulttypediffuse pages 10-11) 66.3% in one WHO2021-classified GBM cohort; editorial cites ~64–82% in molecular subclasses (guo2023histologicalandmolecular pages 1-2, komori2023updateofthe pages 1-2)
WHO CNS5 molecular criterion EGFR amplification Diagnostic molecular feature for GBM, IDH-wildtype; also associated with poorer OS in IDH-wildtype diffuse gliomas/GBM (antonelli2022adulttypediffuse pages 10-11, guo2023histologicalandmolecular pages 1-2) 85.5% in GBM in one real-world study; ~50% cited in review literature; 58.7% in a modern RT/TMZ cohort using FISH/NGS/IHC (antonelli2022adulttypediffuse pages 8-10, hainfellner2024glioblastomainthe pages 1-3)
WHO CNS5 molecular criterion Combined whole chromosome 7 gain / chromosome 10 loss (+7/−10) Diagnostic molecular signature for GBM, IDH-wildtype; often used to identify molecular GBM when histology is lower grade (gue2024the2021world pages 9-12, guo2023histologicalandmolecular pages 1-2, antonelli2022adulttypediffuse pages 10-11) Common hallmark of conventional IDH-wildtype GBM; noted as absent in a rare de novo replication-repair-deficient GBM subtype (guo2023histologicalandmolecular pages 1-2, antonelli2022adulttypediffuse pages 8-10)
Core genomic alteration PTEN loss / deletion / mutation Common tumor-suppressor alteration in PI3K-AKT signaling; generally adverse biology/prognosis, not itself diagnostic under WHO CNS5 (antonelli2022adulttypediffuse pages 10-11) 60% PTEN alterations in one high-grade glioma sequencing cohort; poor-prognosis association reported in IDH-wildtype GBM (hainfellner2024glioblastomainthe pages 1-3, komori2023updateofthe pages 1-2)
Core genomic alteration CDKN2A/B deletion / homozygous deletion Frequent cell-cycle alteration in GBM; adverse prognostic factor in GBM though not a WHO CNS5 stand-alone diagnostic criterion for IDH-wildtype GBM (guo2023histologicalandmolecular pages 1-2, antonelli2022adulttypediffuse pages 10-11) Common alteration in GBM cohorts; in one prognostic study, CDKN2A/B homozygous deletion was statistically significant for worse outcome in GBM (guo2023histologicalandmolecular pages 1-2, komori2023updateofthe pages 1-2)
Predictive biomarker MGMT promoter methylation Predicts better benefit from temozolomide and is associated with improved survival; important for treatment planning, not diagnostic (antonelli2022adulttypediffuse pages 10-11, sahm2023moleculardiagnostictools pages 2-3) 34.3% methylated in Austrian registry; 49.1% methylated in one IDH-wildtype GBM RT/TMZ cohort; associated with better survival in real-world WHO2021 GBM cohort (hainfellner2024glioblastomainthe pages 3-4, hainfellner2024glioblastomainthe pages 1-3, guo2023histologicalandmolecular pages 1-2)
Diagnostic workflow note IDH / H3 exclusion before calling GBM, IDH-wildtype Reviews and algorithms stress confirming IDH-wildtype status and considering H3-altered pediatric-type gliomas, especially in younger patients, before applying molecular GBM criteria (antonelli2022adulttypediffuse pages 10-11, antonelli2022adulttypediffuse media 491d0085) Practical algorithm: if no necrosis/vascular proliferation, test EGFR amplification, TERT promoter mutation, and +7/−10; also evaluate H3 alterations in relevant clinical settings (antonelli2022adulttypediffuse pages 10-11)
Representative clinical-genomic profile Conventional IDH-wildtype GBM landscape Recurrent alterations cluster in RTK/RAS/PI3K, TP53, and RB pathways; EGFR, TERT, PTEN, CDKN2A/B are repeatedly reported as common (antonelli2022adulttypediffuse pages 10-11, guo2023histologicalandmolecular pages 1-2) In WHO2021-classified GBM series: common changes involved chromosomes 1, 7, 9, 10, 19 and EGFR, TERT, CDKN2A/B, PTEN (guo2023histologicalandmolecular pages 1-2)
Important caveat Isolated TERT promoter mutation Supports WHO CNS5 molecular GBM classification, but multiple sources caution that isolated TERTp mutation in a low-grade-appearing diffuse glioma should be interpreted carefully because of limited specificity (antonelli2022adulttypediffuse pages 10-11) Review explicitly states TERT promoter mutation is the least specific of the three WHO molecular criteria (antonelli2022adulttypediffuse pages 10-11)

Table: This table summarizes WHO CNS5 diagnostic rules and major biomarkers for glioblastoma, IDH-wildtype, including their diagnostic, prognostic, or predictive roles. It also gives representative frequencies and practical notes from the cited real-world and review sources.

References (URLs and publication dates)

  • Antonelli & Poliani. Pathologica (2022-12). doi:10.32074/1591-951x-823. https://doi.org/10.32074/1591-951x-823 (antonelli2022adulttypediffuse pages 10-11)
  • Sahm et al. EANO guideline. Neuro-Oncology (2023-06). doi:10.1093/neuonc/noad100. https://doi.org/10.1093/neuonc/noad100 (sahm2023moleculardiagnostictools pages 14-14)
  • Guo et al. WHO2021 real-world reclassification cohort. Frontiers in Oncology (2023-07-06). doi:10.3389/fonc.2023.1200815. https://doi.org/10.3389/fonc.2023.1200815 (guo2023histologicalandmolecular pages 1-2)
  • Bruhn et al. Swedish Brain Tumor Registry (IDH-wildtype GBM). Neuro-Oncology Practice (2024-04). doi:10.1093/nop/npae036. https://doi.org/10.1093/nop/npae036 (bruhn2024dopresentingsymptoms pages 1-2)
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OpenScientist ▸
Glioblastoma, IDH-Wildtype — Comprehensive Disease Characteristics Report
openscientist-autonomous 28 citations 2026-08-20T01:13:52.384587

Glioblastoma, IDH-Wildtype — Comprehensive Disease Characteristics Report

Autonomous discovery investigation • WHO CNS5 (2021) framework • Evidence base: 30 papers reviewed, 2 confirmed findings, 3 supported hypotheses

Summary

Glioblastoma, IDH-wildtype (GBM) is the most common and most aggressive malignant primary brain tumor in adults. Under the 2021 WHO Classification of CNS Tumors (WHO CNS5), it is defined as a WHO grade-4 diffuse astrocytic glioma that is wild-type for IDH1/IDH2 and carries at least one of three molecular hallmarks — TERT promoter mutation, EGFR amplification, or combined whole-chromosome gain of 7 and loss of 10 (+7/−10) — even in the absence of the classic grade-4 histological features of microvascular proliferation or necrosis (so-called "molecular GBM") (PMID: 42159911). This molecular definition marked a fundamental shift away from purely histological diagnosis.

Mechanistically, GBM is a sporadic, somatic-genetic disease. Its driver alterations converge on three core signaling axes — the RTK/PI3K (growth factor), TP53, and RB pathways — with EGFR and CDKN2A/B aberrations found in essentially all tumors, and single-copy PTEN loss plus TERT promoter point mutation acting as the earliest founder events (PMID: 28201779). Downstream, the tumor establishes a profoundly immunosuppressive microenvironment dominated by M2-like tumor-associated macrophages, regulatory T cells, myeloid-derived suppressor cells, and hypoxia-driven tryptophan–kynurenine metabolism that drives T-cell exhaustion — the principal reason immunotherapy has largely failed in GBM.

Clinically, GBM presents in older adults (median age ~64 years, male predominance) with progressive neurological deficits, headache, and seizures. Despite maximal safe surgical resection, radiotherapy, and temozolomide (the Stupp protocol), median overall survival is only ~14.6 months, rising to ~21.7 months when the MGMT promoter is methylated — the single most important predictive/prognostic biomarker (PMID: 41007699). The addition of Tumor Treating Fields (TTFields) to maintenance temozolomide significantly improves survival (pooled HR 0.68 for both OS and PFS) (PMID: 41741710). Five-year survival remains under ~7%. This report synthesizes disease information, etiology, phenotypes, molecular biology, mechanism, anatomy, temporal course, epidemiology, diagnostics, prognosis, treatment, prevention, and model systems for this entity.

Section 1 — Disease Information

Overview. Glioblastoma, IDH-wildtype is a WHO grade-4 diffuse astrocytic tumor of the central nervous system arising from glial or glial-precursor lineage cells. It is characterized histologically (when features are present) by dense cellularity, nuclear atypia, brisk mitotic activity, microvascular/endothelial proliferation, and palisading necrosis, and biologically by diffuse infiltration of surrounding brain parenchyma that renders the tumor surgically incurable. In WHO CNS5 (2021), diagnosis no longer requires these histological features: an IDH-wildtype diffuse astrocytoma with any of the three molecular signatures (TERT promoter mutation, EGFR amplification, +7/−10) is classified as GBM (PMID: 42159911).

Key identifiers. | Resource | Identifier | |---|---| | MONDO | MONDO:0018177 (glioblastoma); IDH-wildtype subtype under adult diffuse glioma | | ICD-O-3 morphology | 9440/3 (glioblastoma, NOS) | | ICD-11 | 2A00.00 (Glioblastoma of brain) | | ICD-10 | C71.x (malignant neoplasm of brain) | | MeSH | D005909 (Glioblastoma) | | OMIM | 137800 (Glioma susceptibility 1) | | SNOMED CT | 63634009 (Glioblastoma multiforme) | | ICD-O-3 (IDH-mutant grade 4, for contrast) | 9445/3 (Astrocytoma, IDH-mutant, grade 4) (PMID: 42581490) |

Synonyms / alternative names. Glioblastoma multiforme (GBM, historical), grade IV astrocytoma, "molecular GBM" (mGBM) when diagnosed by molecular criteria, "histological GBM" (hGBM) when diagnosed by classic morphology, giant cell glioblastoma and gliosarcoma (morphologic patterns). Note the 2021 reclassification removed "IDH-mutant glioblastoma," which is now "Astrocytoma, IDH-mutant, grade 4" — a clinically distinct, better-prognosis entity (PMID: 42581490).

Data source type. The information in this report is drawn from aggregated disease-level resources — WHO classifications, population-based registries (SEER, Spanish and Colombian registries), multicenter cohorts (e.g., the international Histo-Mol GBM Collaborative of 1,857 patients), and mechanistic/omics studies — rather than individual EHR records.

Section 2 — Etiology

Primary causal factors. GBM IDH-wildtype is overwhelmingly a sporadic somatic disease; the vast majority of tumors have no identifiable germline cause. Tumorigenesis is driven by accumulated somatic genomic alterations in glial/precursor cells that activate growth-factor signaling and inactivate tumor-suppressor and cell-cycle control. In multifocal GBM, comprehensive profiling proved monoclonal origin with early founder events (single-copy PTEN loss, TERT promoter mutation) followed by divergent clonal evolution (PMID: 28201779).

Genetic risk factors. - Somatic drivers (not inherited): TERT promoter mutations, EGFR amplification/mutation (incl. EGFRvIII), PTEN loss, CDKN2A/B deletion, TP53 mutation, NF1 loss, PIK3CA/PIK3R1, RB1, PDGFRA, MDM2/4 amplification. - Germline susceptibility (rare): Low-penetrance GWAS loci (e.g., near TERT, EGFR, CDKN2A/B, RTEL1, TP53). Hereditary cancer syndromes predispose to gliomas: Li-Fraumeni (TP53), Lynch/constitutional mismatch-repair deficiency, neurofibromatosis type 1 (NF1), and Turcot syndrome. OMIM 137800 catalogs glioma susceptibility.

Environmental risk factors. - Ionizing radiation to the head (e.g., prior therapeutic cranial irradiation) is the only firmly established exogenous risk factor. - Age (rising incidence with age, peak 65–75), male sex (male predominance; male sex an independent adverse survival factor, HR ~1.37 in one registry) (PMID: 41247425), and European/White ancestry (higher incidence) are demographic risk factors. - No consistent causal role has been established for mobile-phone radiofrequency exposure, occupational chemicals, diet, or head trauma.

Protective factors. Epidemiological studies have repeatedly noted an inverse association with atopic/allergic disease and elevated IgE, suggesting immune surveillance may be protective, though this is correlative. No validated genetic protective allele is established. No dietary or lifestyle factor has robust protective evidence.

Gene–environment interactions. The clearest example is prior therapeutic ionizing radiation interacting with germline DNA-repair deficiency (e.g., mismatch-repair or TP53 pathway defects) to accelerate secondary glioma formation. Otherwise GxE data are sparse for this tumor.

Section 3 — Phenotypes

GBM phenotypes are neurological signs and symptoms produced by mass effect, infiltration, edema, and disruption of eloquent brain regions. Onset is adult/geriatric, course is progressive and typically subacute (symptoms often < 3 months), and severity is moderate-to-severe with major quality-of-life impact.

Phenotype Type HPO term Frequency / notes
Headache Symptom HP:0002315 Very common; often progressive, worse in morning
Seizures Sign/symptom HP:0001250 Seizure at onset in ~25–60%; ~28% (49/177) in one IDH-WT cohort (PMID: 34794192)
Focal motor weakness / hemiparesis Sign HP:0001269 / HP:0002061 Common; slowly progressive neurological deficit (PMID: 29248175)
Aphasia / speech disturbance (dysphasia) Sign HP:0002381 With dominant temporoparietal lesions (PMID: 29062690)
Cognitive/behavioral change Behavioral HP:0000708 Personality change, confusion (PMID: 42607912)
Nausea/vomiting, papilledema (raised ICP) Sign HP:0002017 / HP:0001085 From mass effect and edema
Cognitive decline Symptom HP:0100543 Progressive with tumor growth/treatment

Phenotype–anatomy correlation. In IDH-WT GBM presenting with seizures, lesions are disproportionately located in the parietal lobe, left/dominant hemisphere, and involve the subventricular zone (SVZ); seizure-onset tumors are typically smaller at diagnosis, and generalized seizure at onset associated with longer overall survival (PMID: 34794192). Speech arrest / paroxysmal dysphasia can localize to the dominant temporal lobe (PMID: 29062690).

Quality of life. GBM severely impairs daily functioning through neurological deficits, seizures, fatigue, corticosteroid side effects, and cognitive decline; performance status (KPS) is both a QoL indicator and a strong prognostic factor. Higher intratumoral serotonin was associated with better patient-reported general health in one biobank cohort (PMID: 42377764).

Section 4 — Genetic / Molecular Information

Defining and causal genes (somatic). GBM IDH-wildtype is diagnosed by molecular criteria. Per WHO CNS5, any IDH-wildtype diffuse astrocytoma with TERT promoter mutation, EGFR amplification, or +7/−10 is GBM (PMID: 42159911). The confirmed molecular architecture (Finding F001) is that all tumors harbor alterations across three core pathways:

"All tumors harbored alterations in the 3 GBM core pathways: RTK/PI3K, p53, and RB regulatory pathways with aberrations of EGFR and CDKN2A/B in all (100%) patients." — PMID: 28201779

"Only 2 events were found to be early in all patients: single copy loss of PTEN and TERT promoter point mutations." — PMID: 28201779

Gene (HGNC) Alteration Pathway Consequence
TERT Promoter point mutation (C228T/C250T) Telomere maintenance GoF — telomerase reactivation (early founder)
EGFR Amplification, EGFRvIII, mutation RTK/PI3K GoF — constitutive growth signaling
PTEN Single-copy loss / mutation RTK/PI3K–AKT LoF (early founder)
CDKN2A/B Homozygous deletion RB / cell cycle LoF — loss of p16/p14ARF
TP53 Mutation / MDM2/4 amplification p53 LoF — apoptosis/senescence escape
NF1 Mutation / deletion RTK/RAS LoF — RAS activation
RB1 Deletion / mutation RB LoF — cell-cycle deregulation
PDGFRA, PIK3CA/R1, MET Amplification/mutation RTK/PI3K GoF
Chr 7 gain / Chr 10 loss (+7/−10) Aneuploidy Multiple Diagnostic hallmark

Variant classification / origin. These are somatic alterations (COSMIC/TCGA), not germline; standard ACMG germline pathogenicity classification does not apply. Population allele frequencies (gnomAD) are irrelevant since these arise somatically. Functional consequences are a mix of gain-of-function (EGFR, TERT, PDGFRA amplifications) and loss-of-function (PTEN, CDKN2A/B, TP53, NF1, RB1). EGFR pathway alterations are also prognostically adverse, correlating with rapid early progression (PMID: 41212363).

Epigenetic information. The most clinically important epigenetic mark is MGMT promoter methylation, which silences the DNA-repair enzyme O6-methylguanine-DNA methyltransferase, sensitizing tumors to alkylating chemotherapy (see Sections 10–12). DNA-methylation profiling (methylation-class subgrouping) is increasingly used for diagnosis. GBM lacks the G-CIMP hypermethylator phenotype that characterizes IDH-mutant gliomas.

Modifier genes. MGMT methylation status modifies both chemosensitivity and the survival benefit of surgical cytoreduction (PMID: 41680847). An 11-gene malignant–myeloid interaction signature (incl. TPST1, CHI3L1, NNMT) modifies prognosis and immunotherapy response (PMID: 41838327).

Chromosomal abnormalities. Whole-chromosome +7 gain and −10 loss is near-universal and diagnostic; focal amplifications (EGFR, PDGFRA, MDM2, CDK4/6) and homozygous deletions (CDKN2A/B, PTEN) are frequent. GBM genomes are highly aneuploid.

Section 5 — Environmental Information

  • Environmental factors (CTD/EPA domain): Ionizing radiation is the only established environmental cause. No consistent evidence implicates pesticides, industrial solvents, formaldehyde, or air pollution as causal, though these remain under study.
  • Lifestyle factors: No robust causal lifestyle factor. Smoking, alcohol, and diet have not shown consistent associations. Antidepressant (SSRI) use is common among patients; fluoxetine/sertraline were associated with better survival than other SSRIs (HR 0.62, 95% CI 0.44–0.88) in an observational cohort — hypothesis-generating, not causal (PMID: 42377764).
  • Infectious agents: No pathogen is an established cause. CMV nucleic acids/antigens have been detected in GBM tissue by some groups, but a causal role is unproven and contested. Importantly, cerebral cryptococcoma and other infectious masses can radiologically mimic GBM, a diagnostic pitfall (PMID: 42607912).

Section 6 — Mechanism / Pathophysiology

Molecular pathways. GBM biology is organized around three convergent core pathways (PMID: 28201779): 1. RTK/PI3K–AKT–mTOR growth signaling (EGFR/PDGFRA/MET amplification, PTEN loss, PIK3CA) — GO:0038083, KEGG hsa05214. 2. TP53 apoptosis/senescence axis (TP53 mutation, MDM2/4, CDKN2A/p14ARF) — GO:0072331. 3. RB / cell-cycle control (CDKN2A/B deletion, RB1 loss, CDK4/6, CCND2) — GO:0007049, GO:0000082. Plus telomere maintenance via TERT reactivation — GO:0007004.

Causal chain (upstream → downstream).

Somatic founder events                 Core-pathway convergence            Malignant phenotype
(PTEN loss, TERT promoter mut.)  ─►  RTK/PI3K↑ + p53↓ + RB↓ + TERT↑  ─►  uncontrolled proliferation,
                                                          apoptosis evasion, immortalization
│                                                                         │
▼                                                                         ▼
  Clonal evolution / intratumoral        Angiogenesis (VEGF), hypoxia/           Diffuse infiltration,
  heterogeneity (monoclonal origin) ─►   necrosis, glioma stem cells        ─►   necrosis, microvascular
                                                                 proliferation
                                     │
                                     ▼
            Immunosuppressive tumor microenvironment (TAMs/MDSCs/Treg,
            IDO1–kynurenine, T-cell exhaustion) ─► immune escape, treatment resistance
                                     │
                                     ▼
            Progressive neurological deficits, seizures, death (~14.6 mo)

Cellular processes. Sustained proliferation, evasion of apoptosis, replicative immortality, angiogenesis, invasion/infiltration, and maintenance of a glioma stem-cell compartment. Hypoxia drives pseudopalisading necrosis and VEGF-mediated neovascularization.

Immune system involvement — a defining feature. GBM builds an intensely immunosuppressive TME. Tumor-associated macrophages (M2-like), regulatory T cells, MDSCs, dysfunctional NK and dendritic cells, and exhausted CD8+ T cells cooperate to enforce immune escape; low neoantigen burden, antigenic heterogeneity, and poor immune infiltration further blunt immunity (PMID: 42383800). A hypoxia-driven tryptophan–kynurenine metabolic circuit is central:

"the axis of hypoxia-driven tryptophan degradation … IDO1/TDO2-mediated breakdown of tryptophan and the consequent accumulation of kynurenine, a metabolite that triggers GCN2- and AHR-mediated CD8+ T-cell exhaustion and supports regulatory T-cell differentiation and expansion." — PMID: 41893336

Glial cells (astrocytes, microglia, oligodendrocyte-lineage) spatially organize immune cells into immunosuppressive niches / spatial microdomains that foster local T-cell exhaustion and coordinated immune escape (PMID: 42613643). Malignant–myeloid crosstalk (e.g., an 11-gene signature including TPST1, via PTN–NCL and EREG/AREG–EGFR signaling) shapes the immunosuppressive milieu and predicts poor prognosis/immunotherapy resistance (PMID: 41838327).

Metabolic changes. Aerobic glycolysis (Warburg effect), hypoxia-inducible metabolism, and tryptophan catabolism (IDO1/TDO2 → kynurenine, driving VEGFA via the Trp–GCN2–ATF4 axis, linking immunosuppression to angiogenesis) (PMID: 41893336). Intratumoral serotonin/5-HIAA metabolism is measurable and linked to patient-reported wellbeing (PMID: 42377764).

Tissue damage mechanisms. Oxidative stress, hypoxia/ischemia, pseudopalisading necrosis, blood–brain-barrier breakdown with vasogenic edema, and destruction of eloquent neural tissue.

Molecular profiling & advanced technologies. Multi-omics/single-cell/spatial-transcriptomic studies reveal profound intratumoral heterogeneity and immune spatial architecture (PMID: 41892350, PMID: 42613643). Integrative multi-omics defined the malignant–myeloid interaction signature that outperformed standard clinicopathological factors (PMID: 41838327).

Suggested GO/CL terms. GO:0006954 (inflammatory response), GO:0001525 (angiogenesis), GO:0006979 (response to oxidative stress), GO:0002829/GO:0002534 (immunosuppression); CL:0000878 (CNS macrophage/microglia), CL:0000129 (glial cell), CL:0000784/CL:0000815 (dendritic/regulatory T cell), CL:0000127 (astrocyte), glioma stem cell.

Section 7 — Anatomical Structures Affected

Organ level. Primary organ: the brain (UBERON:0000955), a nervous-system malignancy. Most common site: cerebral hemispheres / supratentorial white matter, especially the frontal and temporal lobes; spread along white-matter tracts and across the corpus callosum ("butterfly glioma") is characteristic (PMID: 29248175). Rare extension to dura, galea, and calvarium (PMID: 29248175). Body system: central nervous system (UBERON:0001017).

Structure UBERON Note
Brain UBERON:0000955 Primary organ
Cerebral hemisphere / cerebrum UBERON:0001869 Most common location
Frontal lobe UBERON:0016525 Frequent
Temporal lobe UBERON:0001871 Frequent; dominant-lobe speech deficits
Parietal lobe UBERON:0001872 Enriched in seizure-onset tumors (PMID: 34794192)
Corpus callosum UBERON:0002336 Butterfly spread
Subventricular zone UBERON:0004024 Putative origin; SVZ involvement in seizure-onset GBM (PMID: 34794192)

Tissue / cell level. Nervous tissue; malignant astrocyte/glial-lineage cells and glioma stem cells; heavy infiltration by tumor-associated macrophages/microglia and other immune cells. CL terms: CL:0000127 (astrocyte), CL:0000129 (glial cell), CL:0000878 (CNS macrophage/microglia).

Subcellular level. Nucleus (GO:0005634 — genomic instability, TP53/RB dysregulation), plasma membrane/cytoplasm (GO:0005886 — EGFR/RTK signaling), mitochondria (GO:0005739 — altered metabolism), telomeres (GO:0000781 — TERT reactivation).

Localization / lateralization. Typically unilateral but diffusely infiltrative and often multilobar (multilobar involvement ~65% on MRI in molecular GBM) (PMID: 41619575); can be multifocal/multicentric (monoclonal) (PMID: 28201779). Left/dominant hemisphere predominance in seizure-onset cases (PMID: 34794192).

Section 8 — Temporal Development

  • Onset: Adult/geriatric; median age ~61–64 years; ~46.5% of patients are ≥65 years (PMID: 42240773). Onset is subacute/insidious, with symptoms typically < 3 months.
  • Progression: Rapid and progressive. GBM is WHO grade 4 (highest grade); there is no formal TNM staging for primary brain tumors. Rapid early progression (REP) — MRI progression after resection but before adjuvant therapy — occurs in ~45–50% and correlates with EGFR pathway alterations (multivariate p=0.006) (PMID: 41212363).
  • Course pattern: Relentlessly progressive; near-universal recurrence after initial therapy. Disease is effectively chronic-lethal over months.
  • Remission / critical periods: True remission is rare; treatment-induced responses are temporary. Timing of chemoradiation initiation matters — starting chemoradiotherapy 32–49 days post-surgery independently improved outcome in MGMT-methylated patients (PMID: 42397615). Prognosis is dynamic — conditional survival improves markedly with time survived (in giant-cell GBM, projected 5-yr survival rose from a 14% baseline to 69–83% among 3–4-year survivors) (PMID: 42189411).

Section 9 — Inheritance and Population

Epidemiology. GBM is the most common malignant primary brain tumor in adults — ~27.9% of malignant CNS tumors in one registry (PMID: 41247425); ~50.1% of high-grade gliomas were IDH-wildtype GBM in a Spanish cohort (PMID: 41133515). Incidence is roughly 3–5 per 100,000 per year and rising in recent series (PMID: 41133515).

Inheritance. Essentially sporadic/somatic; not Mendelian. Susceptibility is multifactorial/polygenic (low-penetrance GWAS loci) with rare high-penetrance familial cancer syndromes (Li-Fraumeni, Lynch/CMMRD, NF1, Turcot). Concepts of penetrance, expressivity, anticipation, mosaicism, founder effects, consanguinity, and carrier frequency are generally not applicable to this somatic tumor except within the rare inherited syndromes.

Population demographics. - Sex: Male predominance (~1.4–1.6:1); male sex an independent adverse prognostic factor (HR ~1.37) (PMID: 41247425). - Age: Peak incidence 65–75; older age strongly worsens survival, with steepest decline ≥70 years (PMID: 42240773). - Ancestry/geography: Higher incidence in White/European-ancestry populations; global data limited, particularly in Latin America (PMID: 41247425).

Section 10 — Diagnostics

Imaging (first-line). Contrast-enhanced MRI is the primary modality: a heterogeneously ring-enhancing mass with central necrosis, surrounding FLAIR-hyperintense vasogenic edema, mass effect, and midline shift. However, molecular GBM often mimics low-grade glioma — enhancement absent in ~39% or faint; infiltrative FLAIR abnormality nearly constant, multilobar in ~65%, diffusion restriction in ~64%, and elevated rCBV (>1.75) in ~88% — so infiltrative FLAIR, multilobar spread, diffusion restriction, or high perfusion should raise suspicion, especially in older patients (PMID: 41619575). Advanced 18F-FDG PET/MRI discriminates high-grade/IDH-wildtype status (SUVmax AUC 0.938; CBF AUC 0.875/0.825) (PMID: 41913661).

Histopathology / IHC (gold standard). Tissue diagnosis via resection or biopsy (biopsy more common in molecular GBM, ~69% vs 30%, and in older/frailer patients) (PMID: 41504931, PMID: 42240773). Histology: pleomorphic astrocytic tumor with mitoses, microvascular proliferation, necrosis. IHC: GFAP+, S-100+, OLIG2+, CD68+ (macrophages), p53 (PMID: 29248175); IDH1 R132H immunonegativity supports IDH-wildtype status.

Molecular/genetic testing (now diagnostic). Required per WHO CNS5: - IDH1/IDH2 status (IHC + sequencing) — must be wild-type. - TERT promoter mutation, EGFR amplification (FISH/NGS), chromosome +7/−10 (CMA/NGS) — any one defines GBM (PMID: 42159911). - MGMT promoter methylation — predictive/prognostic (methylation-specific PCR/pyrosequencing). - CDKN2A/B, PTEN, TP53, NF1, PIK3CA, MTAP via NGS panels — prognostic/therapeutic (PMID: 41212363). - DNA-methylation array classification for difficult cases. Molecular testing is applied less comprehensively in older patients, a care disparity (PMID: 42240773).

Clinical criteria. 2021 WHO CNS5 classification; cIMPACT-NOW updates 8–11 refine the framework (PMID: 42159911).

Differential diagnosis. Brain metastasis, primary CNS lymphoma, IDH-mutant astrocytoma grade 4, oligodendroglioma, abscess, demyelination, and — critically — infectious mass lesions such as cerebral cryptococcoma, which can radiologically mimic high-grade glioma even in immunocompetent hosts (serum/CSF cryptococcal antigen aids differentiation) (PMID: 42607912).

Screening. No population-level screening exists or is recommended; the disease is sporadic, rapidly progressive, and lacks an asymptomatic detectable window.

Section 11 — Outcome / Prognosis

Survival — dismal. Median overall survival with standard care is ~14.6 months overall (Finding F002):

"The standard Stupp protocol (60 Gy/30 fractions with temozolomide [TMZ]) improves overall survival (OS) to 14.6 months, with greater benefits in O6-methylguanine-DNA methyltransferase (MGMT)-methylated tumors (21.7 months)." — PMID: 41007699

5-year survival is ~7% or lower. Real-world median OS was ~12.9 months in a population-based surgical cohort (PMID: 41733819); glioblastoma carried the worst prognosis among CNS tumors in a registry (~20.9% survival in mixed cohorts; HR 9.64) (PMID: 41247425).

Prognostic factors (multiple validated): | Factor | Direction | Evidence | |---|---|---| | MGMT promoter methylation | Favorable (predictive + prognostic) | 21.7 vs 14.6 mo (PMID: 41007699); EF-14 methylated OS 31.6 mo (PMID: 41741710) | | Extent of resection | Favorable | RANO class 1 (supramaximal) OS 21.0 vs 4.5 mo for class 4 (PMID: 41733819) | | Younger age | Favorable | mOS 19.2 (<65) vs 15.0 (≥65) mo (PMID: 40971171) | | Good performance status (KPS/NANO) | Favorable | Preoperatively intact = longer OS (PMID: 41733819) | | Treatment intensity / adjuvant completion | Favorable | Independent predictor (PMID: 42240773) | | EGFR pathway alteration | Adverse (rapid early progression) | REP multivariate p=0.006 (PMID: 41212363) | | Male sex, higher grade | Adverse | HR 1.37 / 7.46 (PMID: 41247425) | | 11-gene malignant–myeloid signature | Adverse; outperforms standard factors | (PMID: 41838327) |

Morbidity/QoL. Progressive neurological disability, seizures, cognitive decline, and dependency; performance status is central to both prognosis and QoL. Prognosis is dynamic — conditional survival improves substantially for those surviving the high-risk early years (PMID: 42189411).

Section 12 — Treatment

Standard of care — the Stupp protocol. Maximal safe surgical resection → concurrent radiotherapy (60 Gy/30 fractions) + temozolomide → adjuvant temozolomide (NCIT: C62554 Temozolomide; C15313 Radiation Therapy; C15329 Surgery). Protocol completion significantly improves OS in both MGMT-methylated and unmethylated patients (p<0.0001) (PMID: 42397615). Optimizations: initiate chemoradiation ~32–49 days post-surgery, add stereotactic sequential boost in methylated patients, minimize dexamethasone (≥1.2 mg/m² worsens outcomes), and avoid age bias (PMID: 42397615).

Tumor Treating Fields (TTFields) (NCIT: C118835). Alternating electric fields added to maintenance TMZ significantly prolong survival (Finding F002, Hypothesis H003):

"Pooled analysis showed that TTFields significantly improved OS, HR = 0.68, 95% CI 0.60–0.78, p < 0.0001" — PMID: 41741710

(also PFS HR 0.68; EF-14 MGMT-methylated median OS 31.6 months).

Pharmacotherapy / pharmacogenomics. Temozolomide is the backbone alkylator; its efficacy depends on MGMT methylation — a pharmacogenomic biomarker where the unmethylated (active) enzyme repairs O6-methylguanine and confers resistance (PMID: 41007699). Bevacizumab (anti-VEGF; NCIT: C2039) is used for recurrence/edema (improves PFS, not OS). Lomustine and other nitrosoureas at recurrence.

Immunotherapy — largely unsuccessful to date. Checkpoint inhibitors, CAR-T, and vaccines have shown limited efficacy owing to the immunosuppressive TME, low neoantigen burden, and antigenic heterogeneity (PMID: 42383800). Emerging strategies combine checkpoint blockade with metabolic reprogramming, myeloid modulation, and interferon reactivation, guided by spatial/single-cell biomarkers (PMID: 41892350). Metabolic-immune targeting (IDO1 inhibitor BMS-986205 + nivolumab + RT) was safe in a phase I trial (RP2D 50 mg; NCT04047706) (PMID: 42189896).

Surgical. Maximal safe / supramaximal resection is a strong independent survival predictor; mild-to-moderate new postoperative deficits did not reduce survival, supporting aggressive resection (PMID: 41733819). Re-resection at recurrence benefits patients, with benefit modulated by MGMT status (greater residual-volume effect in unmethylated tumors) (PMID: 41680847).

Elderly-specific strategy. Fit patients <70 benefit from conventionally fractionated chemoradiation; hypofractionated regimens are appropriate ≥70 (PMID: 42240773). Age alone should not dictate therapy — fit elderly with good KPS and MGMT methylation achieve outcomes similar to younger patients on standard protocols (PMID: 40971171).

Supportive care. Antiepileptics for seizures, corticosteroids (minimized) for edema, rehabilitation, and palliative care.

Personalized medicine. MGMT-stratified surgical and radiotherapy decision-making (PMID: 41680847, PMID: 42397615); NGS-guided identification of EGFR-driven rapid progressors for expedited adjuvant therapy (PMID: 41212363).

Section 13 — Prevention

  • Primary prevention: No established modifiable strategy exists, as GBM lacks proven controllable causes. Avoiding unnecessary therapeutic cranial ionizing radiation is the only rational measure.
  • Secondary prevention / screening: No population screening — rapid progression and lack of an asymptomatic detectable phase make screening impractical.
  • Tertiary prevention: Optimizing treatment (complete resection, protocol completion, TTFields, seizure/edema control, minimizing dexamethasone) to delay progression and preserve function (PMID: 42397615).
  • Immunization / behavioral / public-health / prophylaxis: Not applicable — no vaccine, no validated lifestyle prevention, no infectious cause to interrupt.
  • Genetic counseling: Relevant only for the rare hereditary cancer syndromes (Li-Fraumeni, Lynch/CMMRD, NF1) that predispose to gliomas.

Section 14 — Other Species / Natural Disease

  • Taxonomy: Primarily Homo sapiens (NCBI:txid9606). Naturally occurring glioma is well recognized in dogs (Canis lupus familiaris, NCBI:txid9615), especially brachycephalic breeds (Boxer, Boston Terrier, Bulldog), making canine glioma a valued spontaneous comparative model. Gliomas also occur in cats and other mammals.
  • Breed: Brachycephalic dog breeds are over-represented (VBO breed identifiers apply to canine breeds such as Boxer, Boston Terrier).
  • Orthologous genes: Core drivers are conserved — Egfr, Pten, Tp53, Cdkn2a, Nf1, Rb1, Tert have clear mouse/rat/dog orthologs (NCBI Gene).
  • Comparative biology: Canine gliomas share histological features and some pathway alterations (RTK/PI3K, cell cycle) with human GBM, though molecular concordance is incomplete; they are used to study invasion, imaging, and therapy. Evolutionary conservation of the RTK/PI3K, p53, and RB pathways underlies cross-species relevance.
  • Transmission: Not applicable — GBM is a non-transmissible somatic neoplasm with no zoonotic potential.

Section 15 — Model Organisms

  • Model types: Mammalian in vivo (mouse, rat), cell lines, patient-derived xenografts (PDX), organoids, and iPSC/neural-stem-cell–derived systems.
  • Mouse genetic models: Genetically engineered mouse models (GEMMs) combining core-pathway lesions recapitulate GBM: Nf1/Trp53/Pten conditional knockouts, EGFRvIII transgenics, and RCAS/tv-a and Cre-lox conditional systems targeting glial/neural progenitors. These reproduce diffuse infiltration, necrosis, and the three-pathway (RTK/PI3K, p53, RB) architecture confirmed in human tumors (PMID: 28201779).
  • Xenograft / PDX / organoid models: Human GBM lines (e.g., U87, U251) and glioma-stem-cell–enriched PDX/organoids preserve intratumoral heterogeneity and are used for drug testing; single-cell and spatial platforms increasingly interrogate the immune microenvironment (PMID: 41892350).
  • Phenotype recapitulation: GEMMs and orthotopic models reproduce invasion, angiogenesis, necrosis, and immunosuppressive myeloid infiltration; syngeneic models (GL261, CT-2A) are standard for immunotherapy studies.
  • Limitations: Mouse models incompletely capture human intratumoral/spatial heterogeneity, the mature human immune microenvironment, TERT-promoter biology, and blood–brain-barrier pharmacology — a key reason therapies effective in mice often fail clinically (PMID: 42383800, PMID: 41892350).
  • Resources: MGI, IMPC/KOMP (mouse alleles), Cellosaurus/ATCC (cell lines), and spontaneous canine glioma cohorts (comparative oncology).

Mechanistic Model / Integrated Interpretation

GBM IDH-wildtype is best understood as a convergent somatic-genetic disease with an immunosuppressive systems-level phenotype. Two early founder events (single-copy PTEN loss, TERT promoter mutation) initiate a monoclonal tumor that universally acquires lesions across three core pathways — RTK/PI3K (proliferation/survival), p53 (apoptosis/senescence escape), and RB (cell-cycle deregulation) — with EGFR and CDKN2A/B involved in essentially all tumors (PMID: 28201779). This genomic program yields diffuse infiltration, angiogenesis, hypoxia-driven necrosis, and a glioma-stem-cell reservoir. Downstream, glial cells organize a spatially structured, immunosuppressive microenvironment (M2 TAMs, MDSCs, Treg, IDO1–kynurenine-driven T-cell exhaustion) that enforces immune escape and treatment resistance (PMID: 42613643, PMID: 41893336, PMID: 42383800). Clinically this manifests as older adults with progressive deficits/seizures and a ~14.6-month median survival despite trimodal therapy, with MGMT methylation the dominant lever on chemosensitivity and extent of resection the dominant surgical lever (PMID: 41007699, PMID: 41733819).

Evidence Base — Key Literature

PMID Contribution Support / challenge
42159911 WHO CNS5 molecular definition of GBM Supports F001 / H001
28201779 Three core pathways; EGFR/CDKN2A/B in 100%; PTEN/TERT founders; monoclonal origin Supports F001 / H001
41007699 Stupp OS 14.6 mo; MGMT-methylated 21.7 mo Supports F002 / H002
41741710 TTFields meta-analysis OS/PFS HR 0.68 Supports F002 / H003
42397615 Stupp optimization; timing, dexamethasone, boost Supports treatment section
41733819 Extent of resection & neurological status prognostic Supports prognosis/surgery
41212363 EGFR alterations → rapid early progression Supports temporal/prognosis
42240773 Age, treatment intensity, MGMT predict survival; elderly care Epidemiology/treatment
41504931 mGBM vs hGBM outcomes (WHO CNS5) Disease info/diagnostics
41619575 MRI features of molecular GBM Diagnostics
41913661 FDG-PET/MRI for grade/IDH status Diagnostics
42613643 Glial-organized immune niches Mechanism/immunity
41893336 IDO1–kynurenine → T-cell exhaustion Mechanism/immunity
42383800 Immunosuppressive TME; immunotherapy barriers Mechanism/treatment
41838327 11-gene malignant–myeloid signature; TPST1 Mechanism/prognosis
34794192 Seizure phenotype localization Phenotypes
41247425 Registry epidemiology/prognosis Epidemiology
41133515 Incidence IDH-WT GBM vs IDH-mutant Epidemiology
42607912 Cryptococcoma mimicking GBM Differential dx
42189896 Phase I RT+nivolumab+IDO1 inhibitor Experimental treatment
42581490 WHO 2021 reclassification of IDH-mutant GBM Disease info
42377764 Serotonin/antidepressants, QoL Environmental/QoL
42189411 Conditional survival dynamics Temporal/prognosis
40971171 Elderly on standard protocol Treatment
41680847 MGMT modifies re-resection benefit Treatment
41892350 Precision immunotherapy framework Treatment/mechanism
29248175 Calvarial GBM, IHC markers Anatomy/diagnostics
29062690 Temporal-lobe epilepsy presentation Phenotypes
27893285 Molecular subtyping of CNS tumors Disease info

Limitations and Knowledge Gaps

  1. No primary data analysis. This report is a literature/knowledge synthesis under WHO CNS5; no patient-level dataset was analyzed in the investigation.
  2. Retrospective/observational bias. Much survival and prognostic evidence comes from registries and retrospective cohorts subject to selection and indication bias (e.g., resection favoring fitter patients) (PMID: 41504931).
  3. Immunotherapy mechanisms outpace clinical benefit. Elegant TME biology has not yet translated to survival gains; predictive biomarkers remain unvalidated prospectively (PMID: 42383800, PMID: 41892350).
  4. Etiology largely unexplained. Beyond ionizing radiation and rare syndromes, the causes of sporadic GBM are unknown; no actionable prevention exists.
  5. Underdiagnosis of molecular GBM. mGBM mimics low-grade glioma radiologically, risking treatment delays (PMID: 41619575); molecular testing is applied unevenly, especially in older patients (PMID: 42240773).
  6. Sparse global/LMIC data, particularly outside North America/Europe (PMID: 41247425).

Proposed Follow-up Experiments / Actions

  1. Prospective biomarker-stratified immunotherapy trials integrating spatial/single-cell profiling to select interferon-competent, myeloid-defined subgroups (PMID: 41892350).
  2. Target the hypoxia–tryptophan–kynurenine axis in rational combinations (IDO1/TDO2 + checkpoint + anti-angiogenic), building on the phase I RT+nivolumab+BMS-986205 safety signal (PMID: 42189896, PMID: 41893336).
  3. Validate the 11-gene malignant–myeloid signature (incl. TPST1) prospectively as a prognostic/predictive tool and evaluate TPST1 as a therapeutic target (PMID: 41838327).
  4. EGFR-guided adjuvant acceleration: test whether expediting chemoradiation in EGFR-altered (REP-prone) tumors improves outcomes (PMID: 41212363).
  5. MGMT-stratified surgical/RT algorithms at diagnosis and recurrence in prospective cohorts (PMID: 41680847, PMID: 42397615).
  6. Improve molecular-GBM recognition through radiomic/imaging criteria and universal molecular testing regardless of age (PMID: 41619575, PMID: 42240773).

Confirmed Findings and Hypotheses (from investigation)

Findings - F001: GBM IDH-wildtype is defined molecularly by TERT/EGFR/+7-10 and converges on RTK/PI3K, p53, and RB core pathways (EGFR & CDKN2A/B in 100%; PTEN loss and TERT promoter mutation as early founders) — PMID: 42159911, PMID: 28201779. - F002: Standard therapy yields ~14.6-month median survival; MGMT methylation (21.7 mo) and TTFields (OS/PFS HR 0.68) improve outcomes — PMID: 41007699, PMID: 41741710.

Hypotheses - H001 [supported]: GBM IDH-wildtype defined by core molecular alterations converging on RTK/PI3K, p53, RB pathways. - H002 [supported]: MGMT promoter methylation is a predictive/prognostic biomarker; methylated tumors benefit more from temozolomide. - H003 [supported]: Adding TTFields to maintenance temozolomide improves OS and PFS.

Ontology quick-reference: MONDO:0018177 • MeSH D005909 • ICD-O 9440/3 • ICD-11 2A00.00 • UBERON:0000955 (brain) • CL:0000127 (astrocyte), CL:0000878 (microglia) • GO:0001525 (angiogenesis), GO:0007049 (cell cycle) • CHEBI temozolomide, kynurenine • NCIT C62554 (temozolomide), C118835 (TTFields).

Artifacts

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References weighed for topical relevance 29
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