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Neuro-oncology Aug 2023People with NF1 have an increased prevalence of central nervous system malignancy. However, little is known about the clinical course or pathologic features of...
BACKGROUND
People with NF1 have an increased prevalence of central nervous system malignancy. However, little is known about the clinical course or pathologic features of NF1-associated gliomas in adults, limiting clinical care and research.
METHODS
Adults (≥18 years) with NF1 and histologically confirmed non-optic pathway gliomas (non-OPGs) at Johns Hopkins Hospital, Memorial Sloan Kettering Cancer Center, and Washington University presenting between 1990 and 2020 were identified. Retrospective data were collated, and pathology was reviewed centrally.
RESULTS
Forty-five patients, comprising 23 females (51%), met eligibility criteria, with a median of age 37 (18-68 years) and performance status of 80% (30%-100%). Tissue was available for 35 patients. Diagnoses included infiltrating (low-grade) astrocytoma (9), glioblastoma (7), high-grade astrocytoma with piloid features (4), pilocytic astrocytoma (4), high-grade astrocytoma (3), WHO diagnosis not reached (4) and one each of gliosarcoma, ganglioglioma, embryonal tumor, and diffuse midline glioma. Seventy-one percent of tumors were midline and underwent biopsy only. All 27 tumors evaluated were IDH1-wild-type, independent of histology. In the 10 cases with molecular testing, the most common genetic variants were NF1, EGFR, ATRX, CDKN2A/B, TP53, TERT, and MSH2/3 mutation. While the treatments provided varied, the median overall survival was 24 months [2-267 months] across all ages, and 38.5 [18-109] months in individuals with grade 1-2 gliomas.
CONCLUSIONS
Non-OPGs in adults with NF1, including low-grade tumors, often have an aggressive clinical course, indicating a need to better understand the pathobiology of these NF1-associated gliomas.
Topics: Female; Humans; Adult; Neurofibromatosis 1; Retrospective Studies; Glioma; Astrocytoma; Brain Neoplasms; Disease Progression
PubMed: 36840626
DOI: 10.1093/neuonc/noad033 -
International Journal of Molecular... Nov 2020Astrocytomas and, in particular, their most severe form, glioblastoma, are the most aggressive primary brain tumors and those with the poorest vital prognosis. Standard... (Review)
Review
Astrocytomas and, in particular, their most severe form, glioblastoma, are the most aggressive primary brain tumors and those with the poorest vital prognosis. Standard treatment only slightly improves patient survival. Therefore, new therapies are needed. Very few risk factors have been clearly identified but many epidemiological studies have reported a higher incidence in men than women with a sex ratio of 1:4. Based on these observations, it has been proposed that the neurosteroids and especially the estrogens found in higher concentrations in women's brains could, in part, explain this difference. Estrogens can bind to nuclear or membrane receptors and potentially stimulate many different interconnected signaling pathways. The study of these receptors is even more complex since many isoforms are produced from each estrogen receptor encoding gene through alternative promoter usage or splicing, with each of them potentially having a specific role in the cell. The purpose of this review is to discuss recent data supporting the involvement of steroids during gliomagenesis and to focus on the potential neuroprotective role as well as the mechanisms of action of estrogens in gliomas.
Topics: Animals; Astrocytoma; Disease Progression; Female; Hormones; Humans; Male; Models, Biological; Receptors, Steroid; Sex Characteristics
PubMed: 33266110
DOI: 10.3390/ijms21239114 -
Hematology/oncology Clinics of North... Feb 2022Isocitrate dehydrogenase (IDH) 1 and 2 mutations represent essential components for the diagnosis of diffuse astrocytic tumors and oligodendroglioma. IDH wild-type glial... (Review)
Review
Isocitrate dehydrogenase (IDH) 1 and 2 mutations represent essential components for the diagnosis of diffuse astrocytic tumors and oligodendroglioma. IDH wild-type glial tumors include a wide spectrum of tumors with differences in prognosis and recommended therapeutic approaches. Tumors characterized as molecular glioblastoma in the World Health Organization 2021 classification should be treated according to the glioblastoma therapeutic principles and included in glioblastoma trials. Improving on existing treatments options including targeted and immunotherapy approaches is imperative for most patients with IDH wild-type glial tumors, and enrollment in clinical trials is encouraged.
Topics: Brain Neoplasms; Glioblastoma; Glioma; Humans; Isocitrate Dehydrogenase; Oligodendroglioma
PubMed: 34756799
DOI: 10.1016/j.hoc.2021.08.007 -
Brain Pathology (Zurich, Switzerland) Sep 2023Fusions involving CRAF (RAF1) are infrequent oncogenic drivers in pediatric low-grade gliomas, rarely identified in tumors bearing features of pilocytic astrocytoma, and...
Fusions involving CRAF (RAF1) are infrequent oncogenic drivers in pediatric low-grade gliomas, rarely identified in tumors bearing features of pilocytic astrocytoma, and involving a limited number of known fusion partners. We describe recurrent TRAK1::RAF1 fusions, previously unreported in brain tumors, in three pediatric patients with low-grade glial-glioneuronal tumors. We present the associated clinical, histopathologic and molecular features. Patients were all female, aged 8 years, 15 months, and 10 months at diagnosis. All tumors were located in the cerebral hemispheres and predominantly cortical, with leptomeningeal involvement in 2/3 patients. Similar to previously described activating RAF1 fusions, the breakpoints in RAF1 all occurred 5' of the kinase domain, while the breakpoints in the 3' partner preserved the N-terminal kinesin-interacting domain and coiled-coil motifs of TRAK1. Two of the three cases demonstrated methylation profiles (v12.5) compatible with desmoplastic infantile ganglioglioma (DIG)/desmoplastic infantile astrocytoma (DIA) and have remained clinically stable and without disease progression/recurrence after resection. The remaining tumor was non-classifiable; with focal recurrence 14 months after initial resection; the patient remains symptom free and without further recurrence/progression (5 months post re-resection and 19 months from initial diagnosis). Our report expands the landscape of oncogenic RAF1 fusions in pediatric gliomas, which will help to further refine tumor classification and guide management of patients with these alterations.
Topics: Child; Female; Humans; Adaptor Proteins, Vesicular Transport; Astrocytoma; Brain Neoplasms; Ganglioglioma; Glioma; Oncogene Fusion
PubMed: 37399073
DOI: 10.1111/bpa.13185 -
Neuro-oncology Jun 2022ATRX inactivation occurs with IDH1R132H and p53 mutations in over 80% of Grades II/III astrocytomas. It is believed that ATRX loss contributes to oncogenesis by...
BACKGROUND
ATRX inactivation occurs with IDH1R132H and p53 mutations in over 80% of Grades II/III astrocytomas. It is believed that ATRX loss contributes to oncogenesis by dysregulating epigenetic and telomere mechanisms but effects on anti-glioma immunity have not been explored. This paper examines how ATRX loss contributes to the malignant and immunosuppressive phenotypes of IDH1R132H/p53mut glioma cells and xenografts.
METHODS
Isogenic astrocytoma cells (+/-IDH1R132H/+/-ATRXloss) were established in p53mut astrocytoma cell lines using lentivirus encoding doxycycline-inducible IDH1R132H, ATRX shRNA, or Lenti-CRISPR/Cas9 ATRX. Effects of IDH1R132H+/-ATRXloss on cell migration, growth, DNA repair, and tumorigenicity were evaluated by clonal growth, transwell and scratch assays, MTT, immunofluorence and immunoblotting assays, and xenograft growth. Effects on the expression and function of modulators of the immune microenvironment were quantified by qRT-PCR, immunoblot, T-cell function, macrophage polarization, and flow cytometry assays. Pharmacologic inhibitors were used to examine epigenetic drivers of the immunosuppressive transcriptome of IDH1R132H/p53mut/ATRXloss cells.
RESULTS
Adding ATRX loss to the IDH1R132H/p53mut background promoted astrocytoma cell aggressiveness, induced expression of BET proteins BRD3/4 and an immune-suppressive transcriptome consisting of up-regulated immune checkpoints (e.g., PD-L1, PD-L2) and altered cytokine/chemokine profiles (e.g., IL33, CXCL8, CSF2, IL6, CXCL9). ATRX loss enhanced the capacity of IDH1R132H/p53mut cells to induce T-cell apoptosis, tumorigenic/anti-inflammatory macrophage polarization and Treg infiltration. The transcriptional and biological immune-suppressive responses to ATRX loss were enhanced by temozolomide and radiation and abrogated by pharmacologic BET inhibition.
CONCLUSIONS
ATRX loss activates a BRD-dependent immune-suppressive transcriptome and immune escape mechanism in IDH1R132H/p53mut astrocytoma cells.
Topics: Astrocytoma; Brain Neoplasms; Carcinogenesis; Glioma; Humans; Isocitrate Dehydrogenase; Mutation; Tumor Microenvironment; X-linked Nuclear Protein
PubMed: 34951647
DOI: 10.1093/neuonc/noab292 -
Intractable & Rare Diseases Research Feb 2022Molecular alterations found in gliomas are now considered entity-defining features. The World Health Organization (WHO) classification system currently classifies the...
Molecular alterations found in gliomas are now considered entity-defining features. The World Health Organization (WHO) classification system currently classifies the vast majority of gliomas utilizing an integrated genotype-phenotype approach. We present a case of diffuse astrocytoma with a mosaic isocitrate dehydrogenase (IDH)1-R132H-mutant immunophenotype and low subclonal allele frequency. A 35-year-old patient with a history of -R132H mutated diffuse astrocytoma in 20014 presented to the hospital again in 2019. MRI examination showed a non-enhancing abnormal signal in the periphery of her previous surgical cavity. Histopathological examination revealed that the tumor was hypercellular and without high grade histopathological features. The neoplastic cells were immunohistologically positive for GFAP, Olig2, and ATRX. However, only some scattered tumor cells were positive for -R132H. Cytogenetic studies revealed a lack of chromosomal 1p/19q co-deletion. Further next-generation sequencing (NGS) demonstrated a low-level -R132H mutation and allele frequency. Based on these findings, the diagnosis of diffuse astrocytoma with mosaic - R132H-mutant immunophenotype and low subclonal allele frequency (WHO grade II) was generated. This case indicates that gliomas may have heterogeneous molecular profile and the intra-tumoral molecular heterogeneity highlights the need to further characterize the molecular profile for glioma classification and clinical management.
PubMed: 35261853
DOI: 10.5582/irdr.2022.01019 -
Cells Aug 2022Astrocytes are non-excitable cells in the CNS that can cause life-threatening astrocytoma tumors when they transform to cancerous cells. Perturbed homeostasis of the... (Review)
Review
Astrocytes are non-excitable cells in the CNS that can cause life-threatening astrocytoma tumors when they transform to cancerous cells. Perturbed homeostasis of the neurotransmitter glutamate is associated with astrocytoma tumor onset and progression, but the factors that govern this phenomenon are less known. Herein, we review possible mechanisms by which glutamate may act in facilitating the growth of projections in astrocytic cells. This review discusses the similarities and differences between the morphology of astrocytes and astrocytoma cells, and the role that dysregulation in glutamate and calcium signaling plays in the aberrant morphology of astrocytoma cells. Converging reports suggest that ionotropic glutamate receptors and voltage-gated calcium channels expressed in astrocytes may be responsible for the abnormal filopodiagenesis or process extension leading to astrocytoma cells' infiltration throughout the brain.
Topics: Astrocytes; Astrocytoma; Brain Neoplasms; Glutamic Acid; Humans; Signal Transduction
PubMed: 36078065
DOI: 10.3390/cells11172657 -
Cancer Reports (Hoboken, N.J.) Oct 2023A form of cancer called astrocytoma can develop in the brain or spinal cord and sometimes causes death. A detailed overview of the precise signaling cascade underlying... (Review)
Review
BACKGROUND
A form of cancer called astrocytoma can develop in the brain or spinal cord and sometimes causes death. A detailed overview of the precise signaling cascade underlying astrocytoma formation has not yet been revealed, although various factors have been investigated. Therefore, our objective was to unravel and summarize our current understanding of molecular genetics and associated signaling pathways with some possible therapeutic strategies for astrocytoma.
RECENT FINDINGS
In general, four different forms of astrocytoma have been identified in individuals, including circumscribed, diffuse, anaplastic, and multiforme glioblastoma, according to a recent literature review. All types of astrocytoma have a direct connection with some oncogenic signaling cascade. Common signaling is MAPK cascade, including Ras-Raf-ERK, up-regulated with activating EGFR/AKT/PTEN/mTOR and PDGFR. Recent breakthrough studies found that BRAF mutations, including KIAA1549: BRAF and BRAF V600E are responsible for astrocytoma progression. Additionally, cancer progression is influenced by mutations in some tumor suppressor genes, such as the Tp53/ATRX and MGMT mutant. As synthetic medications must cross the blood-brain barrier (BBB), modulating signal systems such as miRNA is the primary option for treating patients with astrocytoma. However, available surgery, radiation therapy, and experimental therapies such as adjuvant therapy, anti-angiogenic therapy, and EGFR-targeting antibody drug are the usual treatment for most types of astrocytoma. Similar to conventional anticancer medications, some phytochemicals slow tumor growth by simultaneously controlling several cellular proteins, including those involved in cell cycle regulation, apoptosis, metastatic spread, tyrosine kinase, growth factor receptor, and antioxidant-related proteins.
CONCLUSION
In conclusion, cellular and molecular signaling is directly associated with the development of astrocytoma, and a combination of conventional and alternative therapies can improve the malignancy of cancer patients.
Topics: Humans; Proto-Oncogene Proteins B-raf; Brain Neoplasms; Astrocytoma; Glioblastoma; ErbB Receptors
PubMed: 37675821
DOI: 10.1002/cnr2.1889 -
Scientific Reports May 2023Astrocytoma is a common brain tumor that can occur in any part of the central nervous system. This tumor is extremely harmful to patients, and there are no clear studies... (Randomized Controlled Trial)
Randomized Controlled Trial
Astrocytoma is a common brain tumor that can occur in any part of the central nervous system. This tumor is extremely harmful to patients, and there are no clear studies on the risk factors for astrocytoma of the brain. This study was conducted based on the SEER database to determine the risk factors affecting the survival of patients with astrocytoma of the brain. Patients diagnosed with brain astrocytoma in the SEER database from 2004 to 2015 were screened by inclusion exclusion criteria. Final screened brain astrocytoma patients were classified into low grade and high grade according to WHO classification. The risk factors affecting the survival of patients with low-grade and high-grade brain astrocytoma were analyzed by univariate Kaplan-Meier curves and log-rank tests, individually. Secondly, the data were randomly divided into training set and validation set according to the ratio of 7:3, and the training set data were analyzed by univariate and multivariate Cox regression, and the risk factors affecting the survival of patients were screened and nomogram was established to predict the survival rates of patients at 3 years and 5 years. The area under the ROC curve (AUC value), C-index, and Calibration curve are used to evaluate the sensitivity and calibration of the model. Univariate Kaplan-Meier survival curve and log-rank test showed that the risk factors affecting the prognosis of patients with low-grade astrocytoma included Age, Primary site, Tumor histological type, Grade, Tumor size, Extension, Surgery, Radiation, Chemotherapy and Tumor number; risk factors affecting the prognosis of patients with high-grade astrocytoma include Age, Primary site, Tumor histological type, Tumor size, Extension, Laterality, Surgery, Radiation, Chemotherapy and Tumor number. Through Cox regression, independent risk factors of patients with two grades were screened separately, and nomograms of risk factors for low-grade and high-grade astrocytoma were successfully established to predict the survival rate of patients at 3 and 5 years. The AUC values of low-grade astrocytoma training set patients were 0.829 and 0.801, and the C-index was 0.818 (95% CI 0.779, 0.857). The AUC values of patients in the validation set were 0.902, 0.829, and the C-index was 0.774 (95% CI 0.758, 0.790), respectively. The AUC values of high-grade astrocytoma training set patients were 0.814 and 0.806, the C-index was 0.774 (95% CI 0.758, 0.790), the AUC values of patients in the validation set were 0.802 and 0.823, and the C-index was 0.766 (95% CI 0.752, 0.780), respectively, and the calibration curves of the two levels of training set and validation set were well fitted. This study used data from the SEER database to identify risk factors affecting the survival prognosis of patients with brain astrocytoma, which can provide some guidance for clinicians.
Topics: Humans; Nomograms; Risk Factors; Astrocytoma; Brain Neoplasms; Brain; Factor Analysis, Statistical; SEER Program; Prognosis
PubMed: 37173353
DOI: 10.1038/s41598-023-33537-w -
Orphanet Journal of Rare Diseases Dec 2023The randomised double-blinded placebo-controlled EXIST-1-3 studies have showed everolimus effective with adverse effects reported as acceptable in treatment of symptoms... (Clinical Trial)
Clinical Trial
BACKGROUND
The randomised double-blinded placebo-controlled EXIST-1-3 studies have showed everolimus effective with adverse effects reported as acceptable in treatment of symptoms in patients with tuberous sclerosis complex (TSC), although evidence of outcomes in clinical practice remains limited. This study aimed to investigate, in clinical practice, the effectiveness and safety of everolimus for epilepsy, renal angiomyolipoma (rAML), and subependymal giant cell astrocytoma (SEGA) in patients with TSC.
RESULTS
The study included 64 patients with TSC (median age: 19, range 0.9-54 years) receiving everolimus treatment (Norway: n = 35; Denmark: n = 29). Among 45 patients with epilepsy, 14 (31%) were responders experiencing ≥ 50% reduction in seizure frequency in the last 3 months of treatment compared with the last 3 months before treatment. Nineteen (42%) patients changed their anti-seizure medications (ASMs). Responders were more common among patients < 18 years (46%) than among patients ≥ 18 years (14%, p = 0.03). In 29 patients with rAML, everolimus reduced (≥ 30% decrease) and stabilized (< 20% increase, ≤ 30% decrease) longest diameter of rAML in 38% and 59%, respectively, after a mean treatment duration of 37 months. SEGA volume was reduced in three patients by 71%, 43%, and 48% after 39, 34, and 82 months. Adverse effects were reported in 61 of 64 patients (95%) after a median treatment duration of 31 months (range 0-106), with oral ulceration/stomatitis (63%) and upper respiratory tract infections (38%) being the most common. The most common laboratory abnormalities were increased cholesterol (41%), anaemia (30%), and leucopoenia (25%). Grade 3-4 adverse effects were reported in 36% of cases, and life-threatening conditions were reported in two patients. Nine patients discontinued everolimus treatment.
CONCLUSIONS
Seizure reduction in this study sample was consistent with results from EXIST, but might be lower than expected, given that changes in concomitant ASMs are part of clinical practice. Seizure reduction was associated with younger age. As with EXIST, everolimus reduced or stabilised rAML size in most patients. SEGA volume was reduced in all three patients. Close follow-up is needed for this group, especially for children and patients who may not be able to report adverse effects.
Topics: Adolescent; Adult; Child; Child, Preschool; Humans; Infant; Middle Aged; Young Adult; Angiomyolipoma; Antineoplastic Agents; Astrocytoma; Epilepsy; Everolimus; Kidney Neoplasms; Seizures; Tuberous Sclerosis
PubMed: 38042867
DOI: 10.1186/s13023-023-02982-1