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Clinical Cancer Research : An Official... Nov 2023Targeting immunosuppressive and pro-tumorigenic glioblastoma (GBM)-associated macrophages and microglial cells (GAM) has great potential to improve patient outcomes....
PURPOSE
Targeting immunosuppressive and pro-tumorigenic glioblastoma (GBM)-associated macrophages and microglial cells (GAM) has great potential to improve patient outcomes. Colony-stimulating factor-1 receptor (CSF1R) has emerged as a promising target for reprograming anti-inflammatory M2-like GAMs. However, treatment data on patient-derived, tumor-educated GAMs and their influence on the adaptive immunity are lacking.
EXPERIMENTAL DESIGN
CD11b+-GAMs freshly isolated from patient tumors were treated with CSF1R-targeting drugs PLX3397, BLZ945, and GW2580. Phenotypical changes upon treatment were assessed using RNA sequencing, flow cytometry, and cytokine quantification. Functional analyses included inducible nitric oxide synthase activity, phagocytosis, transmigration, and autologous tumor cell killing assays. Antitumor effects and changes in GAM activation were confirmed in a complex patient-derived 3D tumor organoid model serving as a tumor avatar.
RESULTS
The most effective reprogramming of GAMs was observed upon GW2580 treatment, which led to the downregulation of M2-related markers, IL6, IL10, ERK1/2, and MAPK signaling pathways, while M1-like markers, gene set enrichment indicating activated MHC-II presentation, phagocytosis, and T-cell killing were substantially increased. Moreover, treatment of patient-derived GBM organoids with GW2580 confirmed successful reprogramming, resulting in impaired tumor cell proliferation. In line with its failure in clinical trials, PLX3397 was ineffective in our analysis.
CONCLUSIONS
This comparative analysis of CSF1R-targeting drugs on patient-derived GAMs and human GBM avatars identified GW2580 as the most powerful inhibitor with the ability to polarize immunosuppressive GAMs to a proinflammatory phenotype, supporting antitumor T-cell responses while also exerting a direct antitumor effect. These data indicate that GW2580 could be an important pillar in future therapies for GBM.
Topics: Humans; Microglia; Glioblastoma; Macrophages; Brain Neoplasms
PubMed: 37682326
DOI: 10.1158/1078-0432.CCR-23-0576 -
Histology and Histopathology Jul 2023According to the fifth edition of the World Health Organization (WHO) Classification, diffuse gliomas typically occurring in adults are classified as oligodendroglioma... (Review)
Review
According to the fifth edition of the World Health Organization (WHO) Classification, diffuse gliomas typically occurring in adults are classified as oligodendroglioma IDH-mutant and 1p/19q codeleted, astrocytoma IDH-mutant, and glioblastoma IDH-wildtype. Among these, the former has the most favorable clinical course, whereas the latter has the worst prognosis. In IDH-mutant gliomas, the IDH1 p. R132H is the most frequent IDH mutation. Other mutations in IDH1 are rare and predominantly found in astrocytomas, whereas IDH2 mutations are mostly observed in oligodendrogliomas. Astrocytomas IDH-mutant display frequent immunohistochemical loss of ATRX, which is mutually exclusive with 1p/19q codeletion. They are graded based on histopathological features and the presence of CDKN2A/B homozygous deletion, whereas the criteria for grading oligodendrogliomas are less defined. DNA methylation profiling has recently shown three additional distinct tumor types among diffuse IDH-mutant gliomas: infratentorial astrocytoma IDH mutant; primary mismatch repair deficient IDH-mutant astrocytoma (PMRDIA); and oligosarcoma. Infratentorial astrocytoma IDH-mutant is enriched in IDH1 or IDH2 mutations that differ from the IDH1 p.R132H mutation and are detectable only by gene sequencing, displays less frequent ATRX loss and MGMT promoter methylation than supratentorial IDH-mutant astrocytomas, and may additionally harbor the H3 K27M mutation, which is typically found in H3 K27-altered diffuse midline glioma. PMRDIA occurs in the context of primary mismatch repair deficiency, is characterized by frequent MSH6 mutations, hypermutation, low frequency of MGMT promoter methylation, and poor clinical outcomes. Finally, oligosarcoma is a tumor featuring oligodendroglial and sarcomatous areas, and is characterized by worse outcome and frequent 1p/19q copy number loss of heterozygosity.
Topics: Adult; Humans; Oligodendroglioma; Homozygote; Sequence Deletion; Glioma; Brain Neoplasms; Astrocytoma; Mutation; Isocitrate Dehydrogenase; Genomics
PubMed: 36651583
DOI: 10.14670/HH-18-582 -
Clinical Cancer Research : An Official... Dec 2023Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68 to 70 years old. Although advanced age is often...
PURPOSE
Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68 to 70 years old. Although advanced age is often associated with poorer GBM patient survival, the predominant source(s) of maladaptive aging effects remains to be established. Here, we studied intratumoral and extratumoral relationships between adult patients with GBM and mice with brain tumors across the lifespan.
EXPERIMENTAL DESIGN
Electronic health records at Northwestern Medicine and the NCI SEER databases were evaluated for GBM patient age and overall survival. The commercial Tempus and Caris databases, as well as The Cancer Genome Atlas were profiled for gene expression, DNA methylation, and mutational changes with varying GBM patient age. In addition, gene expression analysis was performed on the extratumoral brain of younger and older adult mice with or without a brain tumor. The survival of young and old wild-type or transgenic (INK-ATTAC) mice with a brain tumor was evaluated after treatment with or without senolytics and/or immunotherapy.
RESULTS
Human patients with GBM ≥65 years of age had a significantly decreased survival compared with their younger counterparts. While the intra-GBM molecular profiles were similar between younger and older patients with GBM, non-tumor brain tissue had a significantly different gene expression profile between young and old mice with a brain tumor and the eradication of senescent cells improved immunotherapy-dependent survival of old but not young mice.
CONCLUSIONS
This work suggests a potential benefit for combining senolytics with immunotherapy in older patients with GBM.
Topics: Humans; Animals; Mice; Aged; Glioblastoma; Senotherapeutics; Brain Neoplasms; Mutation; DNA Methylation
PubMed: 37725593
DOI: 10.1158/1078-0432.CCR-23-0834 -
Graefe's Archive For Clinical and... Dec 2023Acute acquired comitant esotropia (AACE) is an uncommon subtype of esotropia characterized by sudden and usually late onset of a relatively large angle of comitant... (Review)
Review
BACKGROUND
Acute acquired comitant esotropia (AACE) is an uncommon subtype of esotropia characterized by sudden and usually late onset of a relatively large angle of comitant esotropia with diplopia in older children and adults.
METHODS
A literature survey regarding neurological pathologies in AACE was conducted using databases (PubMed, MEDLINE, EMBASE, BioMed Central, the Cochrane Library, and Web of Science) in order to collect data for a narrative review of published reports and available literature.
RESULTS
The results of the literature survey were analyzed to provide an overview of the current knowledge of neurological pathologies in AACE. The results revealed that AACE with unclear etiologies can occur in many cases in both children and adults. Functional etiological factors for AACE were found to be due to many reasons, such as functional accommodative spasm, the excessive near work use of mobile phones/smartphones, and other digital screens. In addition, AACE was found to be associated with neurological disorders, such as astrocytoma of the corpus callosum, medulloblastoma, tumors of the brain stem or cerebellum, Arnold-Chiari malformation, cerebellar astrocytoma, Chiari 1 malformation, idiopathic intracranial hypertension, pontine glioma, cerebellar ataxia, thalamic lesions, myasthenia gravis, certain types of seizures, and hydrocephalus.
CONCLUSIONS
Previously reported cases of AACE with unknown etiologies have been reported in both children and adults. However, AACE can be associated with neurological disorders that require neuroimaging probes. The author recommends that clinicians should perform comprehensive neurological assessments to rule out neurological pathologies in AACE, especially in the presence of nystagmus or abnormal ocular and neurological indications (e.g., headache, cerebellar imbalance, weakness, nystagmus, papilloedema, clumsiness, and poor motor coordination).
Topics: Child; Adult; Humans; Esotropia; Arnold-Chiari Malformation; Astrocytoma; Headache; Eye; Acute Disease; Retrospective Studies
PubMed: 37145335
DOI: 10.1007/s00417-023-06092-3 -
AJNR. American Journal of Neuroradiology Jul 2023No qualitative imaging feature currently predicts molecular alterations of pediatric low-grade gliomas with high sensitivity or specificity. The T2-FLAIR mismatch sign...
BACKGROUND AND PURPOSE
No qualitative imaging feature currently predicts molecular alterations of pediatric low-grade gliomas with high sensitivity or specificity. The T2-FLAIR mismatch sign predicts -mutated 1p19q noncodeleted adult gliomas with high specificity. We aimed to assess the significance of the T2-FLAIR mismatch sign in pediatric low-grade gliomas.
MATERIALS AND METHODS
Pretreatment MR images acquired between January 2001 and August 2018 in pediatric patients with pediatric low-grade gliomas were retrospectively identified. Inclusion criteria were the following: 1) 0-18 years of age, 2) availability of molecular information in histopathologically confirmed cases, and 3) availability of preoperative brain MR imaging with non-motion-degraded T2-weighted and FLAIR sequences. Spinal cord tumors were excluded.
RESULTS
Three hundred forty-nine patients were included (187 boys; mean age, 8.7 [SD, 4.8] years; range, 0.5-17.7 years). -B-Raf proto-oncogene () fusion and p.V600E mutation were the most common molecular markers ( = 148, 42%, and = 73, 20.7%, respectively). The T2-FLAIR mismatch sign was present in 25 patients (7.2%). Of these, 9 were dysembryoplastic neuroepithelial tumors; 8, low-grade astrocytomas; 5, diffuse astrocytomas; 1, a pilocytic astrocytoma; 1, a glioneuronal tumor; and 1, an angiocentric glioma. None of the 25 T2-FLAIR mismatch pediatric low-grade gliomas were p.V600E-mutated. Fourteen of 25 pediatric low-grade gliomas with the T2-FLAIR mismatch sign had rare molecular alterations, while the molecular subtype was unknown for 11 tumors.
CONCLUSIONS
The T2-FLAIR mismatch sign was not observed in the common molecular alterations, p.V600E-mutated and fused pediatric low-grade gliomas, while it was encountered in pediatric low-grade gliomas with rare pediatric molecular alterations.
Topics: Adult; Male; Humans; Child; Child, Preschool; Retrospective Studies; Proto-Oncogene Proteins B-raf; Glioma; Brain Neoplasms; Magnetic Resonance Imaging; Astrocytoma; Isocitrate Dehydrogenase; Mutation
PubMed: 37348970
DOI: 10.3174/ajnr.A7916 -
Radiologie (Heidelberg, Germany) Aug 2023Pediatric brain tumors differ regarding location and histopathological features compared to those in adults. In children, 30% of pediatric brain tumors are... (Review)
Review
BACKGROUND
Pediatric brain tumors differ regarding location and histopathological features compared to those in adults. In children, 30% of pediatric brain tumors are supratentorial lesions. Low-grade astrocytomas, e.g. pilocystic astrocytoma or craniopharyngioma, are the most common tumors.
IMAGING MODALITIES
Magnetic resonance imaging (MRI) is the default imaging technique that is used to evaluate the findings. Ultrasound and cranial computed tomography (CCT) accompany the imaging, although CCT is mainly used in emergency situations.
TOPICS COVERED
The following article describes the most common pediatric supratentorial brain tumors with reference to imaging criteria as well as changes in the World Health Organization (WHO) classification.
Topics: Adult; Child; Humans; Brain Neoplasms; Brain; Supratentorial Neoplasms; Astrocytoma; Pituitary Neoplasms
PubMed: 37306748
DOI: 10.1007/s00117-023-01158-z -
Cancer Letters Aug 2023Glioblastoma (GBM) is an aggressive malignant primary brain tumor. Radioresistance largely contributes to poor clinical outcomes in GBM patients. We targeted...
Glioblastoma (GBM) is an aggressive malignant primary brain tumor. Radioresistance largely contributes to poor clinical outcomes in GBM patients. We targeted ribonucleotide reductase subunit 2 (RRM2) with triapine to radiosensitize GBM. We found RRM2 is associated with increasing tumor grade, is overexpressed in GBM over lower grade gliomas and normal tissue, and is associated with worse survival. We found silencing or inhibition of RRM2 by siRNA or triapine sensitized GBM cells to ionizing radiation (IR) and delayed resolution of IR-induced γ-H2AX nuclear foci. In vivo, triapine and IR reduced tumor growth and increased mouse survival. Intriguingly, triapine led to RRM2 upregulation and CHK1 activation, suggesting a CHK1-dependent RRM2 upregulation following RRM2 inhibition. Consistently, silencing or inhibition of CHK1 with rabusertib abolished the triapine-induced RRM2 upregulation. Accordingly, combining rabusertib and triapine resulted in synthetic lethality in GBM cells. Collectively, our results suggest RRM2 is a promising therapeutic target for GBM, and targeting RRM2 with triapine sensitizes GBM cells to radiation and independently induces synthetic lethality of GBM cells with CHK1 inhibition. Our findings suggest combining triapine with radiation or rabusertib may improve therapeutic outcomes in GBM.
Topics: Animals; Mice; Cell Line, Tumor; Glioblastoma; Pyridines; Synthetic Lethal Mutations
PubMed: 37482342
DOI: 10.1016/j.canlet.2023.216308 -
World Neurosurgery May 2024Astrocytoma is a type of adult-type diffuse gliomas that includes diffuse astrocytoma (DA) and anaplastic astrocytoma (AA). However, comprehensive investigations into...
BACKGROUND
Astrocytoma is a type of adult-type diffuse gliomas that includes diffuse astrocytoma (DA) and anaplastic astrocytoma (AA). However, comprehensive investigations into the risk assessment and prognosis of DA and AA using population-based studies remain noticeably scarce.
METHODS
In this study, we developed 2 predictive nomograms to evaluate the susceptibility and prognosis associated with DA and AA. The study cohort comprised 3837 individuals diagnosed with DA or AA between 2010 and 2019 selected from the Surveillance, Epidemiology, and End Results (SEER) database. Independent predictors were identified and used to construct the nomograms for overall death and cancer-specific death rates. The performance of the models was assessed using C-index, calibration curves, and receiver operating characteristic curve, and the clinical applicability was evaluated using decision curve analysis.
RESULTS
The receiver operating characteristic curves in this study show excellent clinical applicability and predictive power. Notably, the area under the curves of the training and verification queues was higher than 0.80, thereby cementing the models' precision. Additionally, the calibration plots demonstrate that the anticipated mortality rates strikingly match the measured values. This alignment of figures is sustained in the validation cohort. Furthermore, the decision curve analysis corroborates the models' translational potential, reinforcing their relevance within real-world clinical settings.
CONCLUSIONS
The presented nomograms have not only exhibited good predictive performance but also showcased pragmatic clinical utility in prognosticating patient outcomes. Significantly, this will undoubtedly serve as a valuable asset for oncologists, facilitating informed treatment decisions and meticulous follow-up planning.
PubMed: 38821404
DOI: 10.1016/j.wneu.2024.05.147 -
Neoplasia (New York, N.Y.) May 2024Alterations in cellular metabolism are important hallmarks of glioblastoma(GBM). Metabolic reprogramming is a critical feature as it meets the higher nutritional demand... (Review)
Review
Alterations in cellular metabolism are important hallmarks of glioblastoma(GBM). Metabolic reprogramming is a critical feature as it meets the higher nutritional demand of tumor cells, including proliferation, growth, and survival. Many genes, proteins, and metabolites associated with GBM metabolism reprogramming have been found to be aberrantly expressed, which may provide potential targets for cancer treatment. Therefore, it is becoming increasingly important to explore the role of internal and external factors in metabolic regulation in order to identify more precise therapeutic targets and diagnostic markers for GBM. In this review, we define the metabolic characteristics of GBM, investigate metabolic specificities such as targetable vulnerabilities and therapeutic resistance, as well as present current efforts to target GBM metabolism to improve the standard of care.
Topics: Humans; Glioblastoma; Brain Neoplasms; Cell Line, Tumor
PubMed: 38479191
DOI: 10.1016/j.neo.2024.100985 -
Acta Neuropathologica Dec 2023Diffuse midline gliomas (DMG) H3 K27-altered are incurable grade 4 gliomas and represent a major challenge in neuro-oncology. This tumour type is now classified in four...
Diffuse midline gliomas (DMG) H3 K27-altered are incurable grade 4 gliomas and represent a major challenge in neuro-oncology. This tumour type is now classified in four subtypes by the 2021 edition of the WHO Classification of the Central Nervous System (CNS) tumours. However, the H3.3-K27M subgroup still appears clinically and molecularly heterogeneous. Recent publications reported that rare patients presenting a co-occurrence of H3.3K27M with BRAF or FGFR1 alterations tended to have a better prognosis. To better study the role of these co-driver alterations, we assembled a large paediatric and adult cohort of 29 tumours H3K27-altered with co-occurring activating mutation in BRAF or FGFR1 as well as 31 previous cases from the literature. We performed a comprehensive histological, radiological, genomic, transcriptomic and DNA methylation analysis. Interestingly, unsupervised t-distributed Stochastic Neighbour Embedding (tSNE) analysis of DNA methylation profiles regrouped BRAF and all but one FGFR1 DMG in a unique methylation cluster, distinct from the other DMG subgroups and also from ganglioglioma (GG) or high-grade astrocytoma with piloid features (HGAP). This new DMG subtype harbours atypical radiological and histopathological profiles with calcification and/or a solid tumour component both for BRAF and FGFR1 cases. The analyses of a H3.3-K27M BRAF tumour at diagnosis and corresponding in vitro cellular model showed that mutation in H3-3A was the first event in the oncogenesis. Contrary to other DMG, these tumours occur more frequently in the thalamus (70% for BRAF and 58% for FGFR1) and patients have a longer overall survival with a median above three years. In conclusion, DMG, H3 K27 and BRAF/FGFR1 co-altered represent a new subtype of DMG with distinct genotype/phenotype characteristics, which deserve further attention with respect to trial interpretation and patient management.
Topics: Adult; Humans; Child; Histones; Brain Neoplasms; Proto-Oncogene Proteins B-raf; Glioma; Astrocytoma; Central Nervous System Neoplasms; Mutation; Receptor, Fibroblast Growth Factor, Type 1
PubMed: 38066305
DOI: 10.1007/s00401-023-02651-4