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Cancer Cell Mar 2020Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these tumors combine...
Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these tumors combine gain-of-function mutations in ACVR1, PIK3CA, and histone H3-encoding genes. The oncogenic mechanisms of action of ACVR1 mutations are currently unknown. Using mouse models, we demonstrate that Acvr1 arrests the differentiation of oligodendroglial lineage cells, and cooperates with Hist1h3b and Pik3ca to generate high-grade diffuse gliomas. Mechanistically, Acvr1 upregulates transcription factors which control differentiation and DIPG cell fitness. Furthermore, we characterize E6201 as a dual inhibitor of ACVR1 and MEK1/2, and demonstrate its efficacy toward tumor cells in vivo. Collectively, our results describe an oncogenic mechanism of action for ACVR1 mutations, and suggest therapeutic strategies for DIPGs.
Topics: Activin Receptors, Type I; Animals; Basic Helix-Loop-Helix Transcription Factors; Bone Morphogenetic Proteins; Brain Neoplasms; Cell Differentiation; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Female; Glioma; Histones; Humans; Lactones; Male; Mice, Transgenic; Mutation; Neoplasms, Experimental; Neuroglia; Oligodendroglia; Receptor, Platelet-Derived Growth Factor alpha; SOXC Transcription Factors
PubMed: 32142668
DOI: 10.1016/j.ccell.2020.02.002 -
Neurologia Medico-chirurgica Mar 2020Diffuse astrocytic and oligodendroglial tumors are frequently associated with symptomatic epilepsy, and predictive seizure control is important for the improvement of...
Diffuse astrocytic and oligodendroglial tumors are frequently associated with symptomatic epilepsy, and predictive seizure control is important for the improvement of patient quality of life. To elucidate the factors related to drug resistance of brain tumor-associated epilepsy from a pathological perspective. From January 2012 to October 2017, 36 patients diagnosed with diffuse astrocytic or oligodendroglial tumors were included. Assessment for seizure control was performed according to the Engel classification of seizures. Patient clinical, radiological, and pathological data were stratified based on the following 16 variables: age, sex, location of tumor, existence of the preoperative seizure, extent of resection, administration of temozolomide, radiation therapy, recurrence, Karnofsky performance scale, isocitrate dehydrogenase 1, 1p/19q co-deletion, Olig2, platelet-derived growth factor receptor alpha, p53, ATRX, and Ki67. These factors were compared between the well-controlled group and drug-resistant seizure group. Twenty-seven patients experienced seizures; of these, 14 cases were well-controlled, and 13 cases were drug-resistant. Neither clinical nor radiological characteristics were significantly different between these two groups, though p53 immunodetection levels were significantly higher, and the frequency of 1p/19q co-deletion was significantly lower in the group with drug-resistant seizures than in the well-controlled group. In the multivariate analysis, only one item was selected according to stepwise methods, and a significant difference was observed for p53 (OR, 21.600; 95% CI, 2.135-218.579; P = 0.009). Upregulation of p53 may be a molecular mechanism underlying drug resistant epilepsy associated with diffuse astrocytic and oligodendroglial tumors.
Topics: Adult; Astrocytoma; Brain Neoplasms; Case-Control Studies; Drug Resistance; Epilepsy; Female; Genes, p53; Humans; Male; Middle Aged; Mutation; Oligodendroglioma; Young Adult
PubMed: 32009124
DOI: 10.2176/nmc.oa.2019-0218 -
International Journal of Epidemiology Mar 2021Central nervous system (CNS) tumours comprise 20% of childhood cancers worldwide. Whether childhood CNS tumour incidence has increased over time across geographic...
BACKGROUND
Central nervous system (CNS) tumours comprise 20% of childhood cancers worldwide. Whether childhood CNS tumour incidence has increased over time across geographic regions remains to be explored.
METHODS
We identified CNS cancers in the Cancer in Five Continents (CI5) data and estimated age standardized incidence rates (ASRs; cases/million children) and 95% confidence intervals (95% CI), male-to-female incidence rate ratios (IRR; 95% CI) and average annual percent change in incidence (AAPC; 95% CI) by geographic region for children aged 0-19 years where data were available using Poisson regression and generalized estimating equations (GEE). Cancers included: astrocytic tumours, medulloblastoma, ependymal, oligodendroglial and mixed glioma, glioma of uncertain origin, and other embryonal tumours. Geographic regions were defined using the United Nations geoscheme.
RESULTS
There were 56 468 CNS cancers included in the study. ASRs were highest for astrocytic tumours globally in 2012 (ASR: 5.83; 95% CI: 5.68-5.99). Globally, all cancers exhibited a male excess in incidence. Regionally, only medulloblastoma had a consistently elevated male-to-female IRR at 1.4-2.2. Globally, incidence decreased for astrocytic tumours in GEE models (AAPC: -1.66; 95% CI: -3.04 to -0.26) and increased for medulloblastoma (AAPC 0.66; 95% CI: 0.19-1.14), ependymal tumours (AAPC: 1.49; 95% CI: 1.49; 95%: 0.69-2.30), glioma of uncertain origin (AAPC: 4.76; 95% CI: 1.17-1.14) and other embryonal tumours (AAPC: 3.58; 95% CI: 2.03-5.15). Regional variation in incidence trends was observed. Countries moving from lower to higher Human Development Index (HDI) over time did not appear to drive observed incidence trends.
CONCLUSIONS
Epidemiologic and molecular studies on underlying mechanisms for changes in the global incidence of CNS tumours are necessary.
Topics: Adolescent; Adult; Central Nervous System Neoplasms; Child; Child, Preschool; Female; Humans; Incidence; Infant; Infant, Newborn; Male; Young Adult
PubMed: 33221912
DOI: 10.1093/ije/dyaa176 -
Neurology India 2020Low grade gliomas (LGG) are most often noted with the unpredictable overall survival and progression to higher grades. Objective: In the present study, we analyze the...
BACKGROUND
Low grade gliomas (LGG) are most often noted with the unpredictable overall survival and progression to higher grades. Objective: In the present study, we analyze the clinicopathological features influencing the prognostic outcomes and compared the features with criteria developed by EORTC.
MATERIALS AND METHODS
We observed the 130 LGG clinical cases in single institute and maintained the follow-up for more than 5 years. In addition, the molecular details were confirmed with markers as IDH, 1p/19q codeletion, p53 and ATRX mutations.
RESULTS
The mean age of patients as 37.67 years and male population contributing to 70%. We observed biased incidence among the male population with dominating occurrence at frontal and parietal lobes in the brain. 40.8% patients had oligodendroglioma, 33.8% astrocytoma, 19.2% oligoastrocytoma and 2.3% gemistocytic astrocytoma pathology. Patients who were subjected to chemotherapy and radiotherapy were noted with average survival of 29 months. Oligodendroglial tumors were found with progression free survival (PFS) of 25 months, oligoastrocytoma cases with 32 months, diffuse astrocytoma cases with 23 months while the gemistocytic astrocytoma cases had 22 months. The PFS for LGG cases was 4.7 years while the overall survival was 4.9 years. Mean survival of patients with KPS score <70 and >70 was 1.5 & 4.9 years respectively. 64 patients were observed with the tumor size >5 cm. In total, 72.3% of the patients were underwent GTR, 23.3% STR and 3.8% underwent biopsy.
CONCLUSION
Taken together, the clinical symptoms, expression of molecular markers and the prognosis details provided by our results can help for better management of LGG cases. We further propose to use following five factors to accurately describe the prognosis and tumor recurrence: 1) Age >50 years, 2) tumor size >5 cm, 3) MIB index >5%, 4) KPS score < 70 and 5) gemistocytic pathology.
Topics: Adult; Astrocytoma; Brain Neoplasms; Glioma; Humans; Male; Middle Aged; Mutation; Neoplasm Recurrence, Local; Oligodendroglioma; Prognosis; Risk Assessment
PubMed: 32859817
DOI: 10.4103/0028-3886.293441 -
Neurology India 2022Diffuse gliomas are represented in the 2007 WHO classification of CNS tumors as astrocytomas, oligoastrocytoma, and oligodendroglioma of grades II/III and glioblastomas...
BACKGROUND
Diffuse gliomas are represented in the 2007 WHO classification of CNS tumors as astrocytomas, oligoastrocytoma, and oligodendroglioma of grades II/III and glioblastomas WHO grade IV, which was a pure morphologic classification. WHO 2016 classification combines morphology with molecular markers like IDH, ATRX, and 1p/19q codeletion to give an integrated diagnosis.
METHODS
The study was carried out on formalin fixed paraffin embedded tissues from 54 patients including three pediatric patients. Molecular studies were performed to know the 1p/19q codeletion status, IDH1R132H, and ATRX immunoexpression. Also, the IDH1R132H status was correlated with survival data.
RESULTS
The study included 54 tumors with oligodendroglial morphology. IDH1R132H positivity was seen in 85% of total cases and codeletion was seen in 72%. The integrated diagnosis revised the cases into oligodendroglioma (39), astrocytoma (5), and glioblastoma (6).IDH mutant tumors were found to have better survival than negative ones which was statistically significant.
CONCLUSION
This study emphasizes the need for molecular work up of tumors with oligodendroglial morphology with readily available techniques like IHC and Fluorescence in situ hybridization.
Topics: Astrocytoma; Brain Neoplasms; Child; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Glioblastoma; Glioma; Humans; In Situ Hybridization, Fluorescence; Isocitrate Dehydrogenase; Molecular Typing; Mutation; Oligodendroglioma
PubMed: 35864633
DOI: 10.4103/0028-3886.349641 -
Applied Immunohistochemistry &... Mar 2022Patients below 55 years were genetically studied because the prevalence of isocitrate dehydrogenase 1 (IDH1) decreases in older patients and on grounds of...
Patients below 55 years were genetically studied because the prevalence of isocitrate dehydrogenase 1 (IDH1) decreases in older patients and on grounds of cost-effectiveness, as suggested by the World Health Organization (WHO) in 2016. The aim of our study was to use novel massively parallel sequencing (MPS) approaches to examine rare variants of IDH1/2 in Czech diffuse astrocytic and oligodendroglial tumors (gliomas) patients below 55 years of age who had been immunohistochemically (IHC) diagnosed as IDH1 R132H negative. The IHC IDH1 status (wild type or mutant) of 275 tissue samples was analyzed using antibodies against the IDH1 R132H protein. Sixty-three samples of 55 years old patients with IHC IDH1 WT status were genotyped using two different MPS technologies to detect rare IDH1 and IDH2 variants. The tiered IHC (60 positive) and molecular (10 positive) approach thus revealed that 70 of the 275 samples (25%) bore IDH1/IDH2 mutations. The combined molecular and IHC approach thus revealed that 70 of the 275 samples (25%) considered in the study bore IDH1/IDH2 mutations. IHC detection of the IDH1 R132H variant should be routinely complemented with MPS to detect rare IDH1/2 variants in glioma patients below 55 years of age with negative IHC result of IDH R132H variant.
Topics: Aged; Brain Neoplasms; Glioma; High-Throughput Nucleotide Sequencing; Humans; Isocitrate Dehydrogenase; Middle Aged; Mutation; Retrospective Studies
PubMed: 35262523
DOI: 10.1097/PAI.0000000000000997 -
Scientific Reports May 2020Mutations in isocitrate dehydrogenase genes IDH1 and IDH2 are frequently found in diffuse and anaplastic astrocytic and oligodendroglial tumours as well as in secondary...
Mutations in isocitrate dehydrogenase genes IDH1 and IDH2 are frequently found in diffuse and anaplastic astrocytic and oligodendroglial tumours as well as in secondary glioblastomas. As IDH is a very important prognostic, diagnostic and therapeutic biomarker for glioma, it is of paramount importance to determine its mutational status. The haematoxylin and eosin (H&E) staining is a valuable tool in precision oncology as it guides histopathology-based diagnosis and proceeding patient's treatment. However, H&E staining alone does not determine the IDH mutational status of a tumour. Deep learning methods applied to MRI data have been demonstrated to be a useful tool in IDH status prediction, however the effectiveness of deep learning on H&E slides in the clinical setting has not been investigated so far. Furthermore, the performance of deep learning methods in medical imaging has been practically limited by small sample sizes currently available. Here we propose a data augmentation method based on the Generative Adversarial Networks (GAN) deep learning methodology, to improve the prediction performance of IDH mutational status using H&E slides. The H&E slides were acquired from 266 grade II-IV glioma patients from a mixture of public and private databases, including 130 IDH-wildtype and 136 IDH-mutant patients. A baseline deep learning model without data augmentation achieved an accuracy of 0.794 (AUC = 0.920). With GAN-based data augmentation, the accuracy of the IDH mutational status prediction was improved to 0.853 (AUC = 0.927) when the 3,000 GAN generated training samples were added to the original training set (24,000 samples). By integrating also patients' age into the model, the accuracy improved further to 0.882 (AUC = 0.931). Our findings show that deep learning methodology, enhanced by GAN data augmentation, can support physicians in gliomas' IDH status prediction.
Topics: Adult; Aged; Deep Learning; Female; Glioma; Humans; Isocitrate Dehydrogenase; Magnetic Resonance Imaging; Male; Middle Aged; Mutation; Prognosis
PubMed: 32382048
DOI: 10.1038/s41598-020-64588-y -
Neurologia Medico-chirurgica Apr 2022Malignant progression of diffuse low-grade glioma (LGG) is a critical event affecting patient survival; however, the incidence and related factors have been inconsistent... (Meta-Analysis)
Meta-Analysis
Malignant progression of diffuse low-grade glioma (LGG) is a critical event affecting patient survival; however, the incidence and related factors have been inconsistent in literature. According to the PRISMA guidelines, we systematically reviewed articles from 2009, meta-analyzed the incidence of malignant progression, and clarified factors related to the transformation. Forty-one articles were included in this study (n = 7,122; n, number of patients). We identified two definitions of malignant progression: histologically proven (Htrans) and clinically defined (Ctrans). The malignant progression rate curves of Htrans and Ctrans were almost in parallel when constructed from the results of meta-regression by the mean follow-up time. The true transformation rate was supposed to lie between the two curves, approximately 40% at the 10-year mean follow-up. Risk of malignant progression was evaluated using hazard ratio (HR). Pooled HRs were significantly higher in tumors with a larger pre- and postoperative tumor volume, lower degree of resection, and notable preoperative contrast enhancement on magnetic resonance imaging than in others. Oligodendroglial histology and IDH mutation (IDHm) with 1p/19q codeletion (Codel) also significantly reduced the HRs. Using Kaplan-Meier curves from eight studies with molecular data, we extracted data and calculated the 10-year malignant progression-free survival (10yMPFS). The 10yMPFS in patients with IDHm without Codel was 30.4% (95% confidence interval [95% CI]: 22.2-39.0) in Htrans and 38.3% (95% CI: 32.3-44.3) in Ctrans, and that with IDHm with Codel was 71.7% (95% CI: 61.7-79.5) in Htrans and 62.5% (95% CI: 55.9-68.5) in Ctrans. The effect of adjuvant radiotherapy or chemotherapy could not be determined.
Topics: Brain Neoplasms; Glioma; Humans; Incidence; Isocitrate Dehydrogenase; Mutation
PubMed: 35197400
DOI: 10.2176/jns-nmc.2021-0313 -
PloS One 2020Despite many years of research efforts and clinical trials the prognosis of patients diagnosed with glioblastoma remains very poor. The oligodendrocyte transcription...
Despite many years of research efforts and clinical trials the prognosis of patients diagnosed with glioblastoma remains very poor. The oligodendrocyte transcription factor 2 (Olig2) was identified as a marker for glioma stem cells, which are believed to be responsible for glioma recurrence and therapy resistance. In this retrospective analysis we assessed the prognostic value of oligodendroglial and glioma stem cell markers in 113 IDH-wildtype glioblastomas. Immunohistochemical staining for Olig2, NogoA, AQP4 and Nestin was performed in combination with sequencing of IDH1 and IDH2 as well as promotor methylation analysis of the MGMT gene. Even though differences in overall survival according to Olig2 expression were observed, univariate and multivariate survival analysis did not reveal a firm significant prognostic impact of Olig2, NogoA, AQP4 or Nestin expression. Additionally, no differences in the expression of these markers depending on clinical status, age or gender were found. The established independent prognostic factors age<65, Karnofsky Performance Status> = 70 and methylated MGMT gene promoter were significant in the multivariate analysis. In conclusion expression of oligodendroglial and glioma stem cell markers do not have an independent prognostic effect in IDH-wildtype glioblastoma.
Topics: Adult; Aged; Aged, 80 and over; Aquaporin 4; Biomarkers, Tumor; Brain Neoplasms; Female; Glioblastoma; Humans; Isocitrate Dehydrogenase; Male; Middle Aged; Mutation; Neoplasm Recurrence, Local; Nestin; Nogo Proteins; Oligodendrocyte Transcription Factor 2; Prognosis; Promoter Regions, Genetic; Retrospective Studies; Young Adult
PubMed: 32160197
DOI: 10.1371/journal.pone.0229274 -
Asian Pacific Journal of Cancer... May 2023Prostate-specific membrane antigen (PSMA) was first noticed in prostate cancer cells, thereafter, It has been found in the endothelial cells of neovasculature in a...
BACKGROUND
Prostate-specific membrane antigen (PSMA) was first noticed in prostate cancer cells, thereafter, It has been found in the endothelial cells of neovasculature in a variety of tumors, but not in normal vascular endothelium, This specificity makes PSMA an ideal molecule for vascular targeting in Cancer theranostics (i.e., combined diagnostic and therapeutic).
OBJECTIVES
The objective of this study was to evaluate the immunohistochemical (IHC) expression of PSMA in the neovasculature (identified by CD 31) of high-grade gliomas (HGGs) and to Correlate PSMA IHC expression in HGGs with clinicopathological features, to detect its possible role in tumor angiogenesis, where PSMA can be used as a future diagnostic and therapeutic target.
MATERIALS AND METHODS
This retrospective study included a total of 69 archived, formalin-fixed, paraffin-embedded tissue blocks of HGGs, including 52 cases classified as WHO grade IV (75.4%) and 17 cases as WHO grade III (24.6%). The samples were immunohistochemically analyzed for PSMA expression (in both TMV and parenchymal tumor cells) which was assessed using the composite PSMA immunostaining score. A score (0) was considered negative while scores 1-7 were considered positive (1-4, 5-6, or 7; weak, moderate, or strong respectively).
RESULTS
PSMA is expressed specifically and significantly in endothelial cells of tumor microvessels (TMV) of HGGs, A statistically significant relationship was detected between PSMA IHC expression in both TMV and in parenchymal tumor cells (TC) and various glioma subtypes (P-value < 0.05 and <0.001 respectively). Positive PSMA immunostaining in TMV was detected in all anaplastic ependymoma cases and in near all cases of classic GB and GB with oligodendroglial features more than other subtypes, with P-value specifically for PSMA positivity/negativity in TMV statistically significant (0.022). While for Tumor cells, Positive PSMA immunostaining was detected in all anaplastic ependymoma, most anaplastic astrocytoma and classic GB cases in contrary to other variants, with P-value statistically extremely significant (< 0.001). Comparing PSMA IHC expression in TMV and its expression in TC, it was significantly expressed in TMV of 82.7% versus TC of 51.9% of grade IV cases. Likewise, in GB with oligodendroglial features and gliosarcoma, the majority of cases showed positive staining in their TMV [8/8 (100%), 9/13 (69.2%) respectively], and, the reverse occurs in tumor cells where the majority of cases did NOT show staining in the tumor cells for PSMA (5/8 (62.5%), 11/13 (84.6%) of cases respectively), which was statistically significant (P-value ≤ 0.05) besides the significant difference in the pattern of staining according to composite PSMA scoring (P-value ≤ 0.05).
CONCLUSION
PSMA has a possible role in tumor angiogenesis, therefore it might be considered a potential promising endothelial target for Cancer theranostics with PSMA-based agents, in addition, PSMA was expressed significantly in TC of HGGs, thus, it appears to be involved in biologic behavior, carcinogenesis and tumor progression.
Topics: Humans; Male; Antigens, Surface; Endothelial Cells; Ependymoma; Glioma; Glutamate Carboxypeptidase II; Neovascularization, Pathologic; Prostate; Prostatic Neoplasms; Retrospective Studies
PubMed: 37247303
DOI: 10.31557/APJCP.2023.24.5.1797