Molecular Markers in Low-Grade Glioma-Toward Tumor Reclassification.
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ABSTRACT:
SUBMITTER: Olar A
PROVIDER: S-EPMC4500036 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Low grade gliomas are the most frequent brain tumors in children and encompass a spectrum of histologic entities which are currently assigned World Health Organisation grades I and II. They differ substantially from their adult counterparts in both their underlying genetic alterations and in the infrequency with which they transform to higher grade tumors. Nonetheless, children with low grade glioma are a therapeutic challenge due to the heterogeneity in their clinical behavior - in particular, those with incomplete surgical resection often suffer repeat progressions with resultant morbidity and, in some cases, mortality. The identification of up-regulation of the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway as a near universal feature of these tumors has led to the development of targeted therapeutics aimed at improving responses while mitigating patient morbidity. Here, we review how molecular information can help to further define the entities which fall under the umbrella of pediatric-type low-grade glioma. In doing so we discuss the specific molecular drivers of pediatric low grade glioma and how to effectively test for them, review the newest therapeutic agents and their utility in treating this disease, and propose a risk-based stratification system that considers both clinical and molecular parameters to aid clinicians in making treatment decisions.
| S-EPMC7066826 | biostudies-literature
Project description:BACKGROUND: The current therapy of malignant gliomas is based on surgical resection, radio-chemotherapy and chemotherapy. Recent retrospective case-series have highlighted the significance of the extent of resection as a prognostic factor predicting the course of the disease. Complete resection in low-grade gliomas that show no MRI-enhanced images are especially difficult. The aim in this study was to develop a robust, specific, new fluorescent probe for glioma cells that is easy to apply to live tumor biopsies and could identify tumor cells from normal brain cells at all levels of magnification. METHODOLOGY/PRINCIPAL FINDINGS: In this investigation we employed brightly fluorescent, photostable quantum dots (QDs) to specifically target epidermal growth factor receptor (EGFR) that is upregulated in many gliomas. Living glioma and normal cells or tissue biopsies were incubated with QDs coupled to EGF and/or monoclonal antibodies against EGFR for 30 minutes, washed and imaged. The data include results from cell-culture, animal model and ex vivo human tumor biopsies of both low-grade and high-grade gliomas and show high probe specificity. Tumor cells could be visualized from the macroscopic to single cell level with contrast ratios as high as 1000: 1 compared to normal brain tissue. CONCLUSIONS/SIGNIFICANCE: The ability of the targeted probes to clearly distinguish tumor cells in low-grade tumor biopsies, where no enhanced MRI image was obtained, demonstrates the great potential of the method. We propose that future application of specifically targeted fluorescent particles during surgery could allow intraoperative guidance for the removal of residual tumor cells from the resection cavity and thus increase patient survival.
| S-EPMC2894859 | biostudies-literature
Project description:To examine the effect of Nf1 inactivation in astrocytes on normal microglia in the optic nerve, microglia from Nf1 flox/flox (FF) and Nf1 flox/flox; GFAP-Cre (FFC) were flow sorted. High throughput RNA-seq was employed to compare the expression profiles, and upregulated genes in microglia supportive to Nf1 deficient astrocytes were verified.
2020-07-03 | GSE65865 | GEO
Project description:BackgroundSeveral studies reported a correlation between anatomic location and genetic background of low-grade gliomas (LGGs). As such, tumor location may contribute to presurgical clinical decision-making. Our purpose was to visualize and compare the spatial distribution of different WHO 2016 gliomas, frequently aberrated single genes and DNA copy number alterations within subgroups, and groups of postoperative tumor volume.MethodsAdult grade II glioma patients (WHO 2016 classified) diagnosed between 2003 and 2016 were included. Tumor volume and location were assessed with semi-automatic software. All volumes of interest were mapped to a standard reference brain. Location heatmaps were created for each WHO 2016 glioma subgroup, frequently aberrated single genes and copy numbers (CNVs), as well as heatmaps according to groups of postoperative tumor volume. Differences between subgroups were determined using voxelwise permutation testing.ResultsA total of 110 IDH mutated astrocytoma patients, 92 IDH mutated and 1p19q co-deleted oligodendroglioma patients, and 22 IDH wild-type astrocytoma patients were included. We identified small regions in which specific molecular subtypes occurred more frequently. IDH-mutated LGGs were more frequently located in the frontal lobes and IDH wild-type tumors more frequently in the basal ganglia of the right hemisphere. We found no localizations of significant difference for single genes/CNVs in subgroups, except for loss of 9p in oligodendrogliomas with a predilection for the left parietal lobes. More extensive resections in LGG were associated with frontal locations.ConclusionsWHO low-grade glioma subgroups show differences in spatial distribution. Our data may contribute to presurgical clinical decision-making in LGG patients.
| S-EPMC8051437 | biostudies-literature
Project description:Purpose of reviewPediatric low-grade gliomas (pLGGs) have been treated with similar therapies for the last 30 years. Recent biological insights have allowed a new generation of targeted therapies to be developed for these diverse tumors. At the same time, technological advances may redefine the late toxicities associated with radiation therapy. Understanding recent developments in pLGG therapy is essential to the management of these common pediatric tumors.Recent findingsIt is now well understood that aberrations of the mitogen-activated protein kinase pathway are key to oncogenesis in low-grade gliomas. This understanding, along with the development of available targeted agents, have heralded a new era of understanding and treatment for these patients. Promising, sustained responses are now being seen in early phase trials among patients with multiply recurrent/progressive disease. Also, newer and highly conformal radiation approaches such as proton beam radiotherapy maintain efficacy of radiation but limit radiation-associated toxicities.SummaryNovel therapies offer the potential for tumor control with greatly reduced toxicities. However, late effects of these therapies are just now being explored. Improved radiation approaches and targeted agents have the potential to redefine traditional therapy for pLGG.
| S-EPMC6664811 | biostudies-literature
Project description:BackgroundManagement of unresectable pediatric low-grade glioma and glioneuronal tumor (LGG/LGGNT) is controversial. There are no validated prognostic features to guide use of radiation therapy (RT). Our study aimed to identify negative prognostic features in patients treated with RT using clinicopathologic and molecular data and validate these findings in an external dataset.MethodsChildren with non-metastatic, biopsy-proven unresectable LGG/LGGNT treated with RT at a single institution between 1997 and 2017 were identified. Recursive partitioning analysis (RPA) was used to stratify patients into low- and high-risk prognostic groups based on overall survival (OS). CNS9702 data were used for validation.ResultsOne hundred and fifty patients met inclusion criteria. Median follow-up was 11.4 years. RPA yielded low- and high-risk groups with 10-year OS of 95.6% versus 76.4% (95% CI: 88.7%-98.4% vs 59.3%-87.1%, P = 0.003), respectively. These risk groups were validated using CNS9702 dataset (n = 48) (4-year OS: low-risk vs high-risk: 100% vs 64%, P < 0.001). High-risk tumors included diffuse astrocytoma or location within thalamus/midbrain. Low-risk tumors included pilocytic astrocytoma/ganglioglioma located outside of the thalamus/midbrain. In the subgroup with known BRAF status (n = 49), risk stratification remained prognostic independently of BRAF alteration (V600E or fusion). Within the high-risk group, delayed RT, defined as RT after at least one line of chemotherapy, was associated with a further decrement in overall survival (P = 0.021).ConclusionA high-risk subgroup of patients, defined by diffuse astrocytoma histology or midbrain/thalamus tumor location, have suboptimal long-term survival and might benefit from timely use of RT. These results require validation.
| S-EPMC7594561 | biostudies-literature
Project description:BACKGROUND:The neurologic outcomes of low-grade gliomas (LGGs) according to tumor location and duration of presenting symptoms remain poorly characterized in children. PROCEDURE:We retrospectively reviewed neurologic impairments in 246 pediatric patients with LGGs (88 with optic pathway and midline tumors, 56 with posterior fossa tumors, 52 with cerebral hemisphere tumors, 35 with brainstem tumors, and 15 with spinal cord tumors) who were treated at St. Jude Children's Research Hospital between 1995 and 2005. We compared neurologic impairments (defined by Common Terminology Criteria for Adverse Events, version 4.03) by tumor location and prediagnosis symptom interval (PSI) (??3 months or <?3 months) at first and last patient visits. RESULTS:The median age of diagnosis was 7.1 years; median PSI was 2.1 months; and median time to last follow-up was 11.6 years. LGGs in the cerebral hemispheres resulted in significantly fewer neurologic impairments, compared with that of other locations at baseline (P < 0.001) and at last follow-up (P < 0.001). In all patients, PSIs greater than 3 months resulted in a significantly higher incidence of ataxia and dysmetria at last follow-up (42%, P = 0.003). Greater PSI was also significantly associated with worsening lower extremity motor weakness from cerebral hemisphere tumors; dysmetria from optic pathway and midline tumors; eye and visual dysfunction from posterior fossa tumors; and ear and vestibular disturbances from brainstem tumors (P???0.05). CONCLUSION:Neurologic impairment in pediatric LGGs varies by tumor location, and PSIs greater than 3 months affect some functionally important neurologic outcomes.
| S-EPMC6310055 | biostudies-literature
Project description:BackgroundColorectal tumor differentially expressed (CRNDE) is specifically expressed in human brains and is the most highly expressed lncRNA in gliomas. Nevertheless, its implications in low grade glioma (LGG) are still indistinct. This study presented systematic analyses of CRNDE in LGG biology.MethodsWe retrospectively retrieved TCGA, CGGC and GSE16011 LGG cohorts. Survival analysis was conducted for evaluating the prognostic significance of CRNDE in LGG. A CRNDE-based nomogram was established, and its predictive performance was verified. Signaling pathways underlying CRNDE were analyzed through ssGSEA and GSEA approaches. The abundance of immune cells and activity of cancer-immunity cycle were estimated with ssGSEA approach. Immune checkpoints, HLAs, chemokines, and immunotherapeutic response indicators (TIDE, and TMB) was quantified. U251 and SW1088 cells were transfected with specific shRNAs of CRNDE, and flow cytometry (apoptosis) and western blot (β-catenin and Wnt5a) assays were conducted.ResultsUp-regulated CRNDE was found in LGG, and was linked to unfavorable clinical outcomes. The CRNDE-based nomogram enabled to accurately predict patients' prognosis. High CRNDE expression was linked to more genomic variations, activity of tumorigenic pathways, tumor immunity (increase in infiltration of immune cells, expression of immune checkpoints, HLAs and chemokines, and cancer-immunity cycle), and therapeutic sensitivity. CRNDE knockdown mitigated malignant phenotypes of LGG cells.ConclusionsOur study determined CRNDE as a novel predictor for patient prognosis, tumor immunity and therapeutic response in LGG. Assessment of CRNDE expression is a promising approach for predicting the therapeutic benefits of LGG patients.
| S-EPMC10186690 | biostudies-literature
Project description:Background:Diffuse low-grade gliomas (DLGGs) are rare and incurable tumors. Whereas maximal safe, functional-based surgical resection is the first-line treatment, the timing and choice of further treatments (chemotherapy, radiation therapy, or combined treatments) remain controversial. Methods:An online survey on the management of DLGG patients was sent to 28 expert centers from the European Low-Grade Glioma Network (ELGGN) in May 2015. It contained 40 specific questions addressing the modalities of use of chemotherapy in these patients. Results:The survey demonstrated a significant heterogeneity in practice regarding the initial management of DLGG patients and the use of chemotherapy. Interestingly, radiation therapy combined with the procarbazine, CCNU (lomustine), and vincristine regimen has not imposed itself as the gold-standard treatment after surgery, despite the results of the Radiation Therapy Oncology Group 9802 study. Temozolomide is largely used as first-line treatment after surgical resection for high-risk DLGG patients, or at progression. Conclusions:The heterogeneity in the management of patients with DLGG demonstrates that many questions regarding the postoperative strategy and the use of chemotherapy remain unanswered. Our survey reveals a high recruitment potential within the ELGGN for retrospective or prospective studies to generate new data regarding these issues.
| S-EPMC6660823 | biostudies-literature
Project description:This study aimed to assess the incidence and management of pseudoprogression after radiation therapy (RT) in patients with pediatric low-grade glioma (LGG). This retrospective review included patients aged 21 years or younger with intracranial LGG treated with curative-intent RT. Pseudoprogression was defined as an increase in tumor size by ≥10% in at least two dimensions between two and three consecutive MR imaging studies. Overall survival (OS) and event-free survival (EFS) were measured from the first day of RT. EFS was defined as survival without true progression or secondary high-grade glioma. Sixty-two of 221 patients developed pseudoprogression, with a 10-year cumulative incidence of 29.0% (95% CI 23.0-35.2). Median time to pseudoprogression was 6.1 months after RT. Symptomatic pseudoprogression was managed with subtotal resection, shunt/Ommaya reservoir placement, or corticosteroids in 11 (18%), 7 (11%), and 2 patients (3%), respectively. The remaining tumors were observed (68%). Patients with pilocytic astrocytoma (PA) had 5.4-fold greater odds of developing pseudoprogression relative to tumors of other histology (odds ratio 95% CI 2.5-11.4, P < 0.0001). Among patients with PA (n = 127), the 10-year cumulative incidence of pseudoprogression was 42.9%. In this group, pseudoprogression was associated with improved 10-year EFS (84.5% vs. 58.5%, P = 0.008) and OS (98.0% vs. 91.2%, P = 0.03). Pseudoprogression after irradiation was common, especially in patients with pilocytic astrocytoma, and was associated with improved survival. Knowledge of the incidence and temporal course of pseudoprogression may help avoid unnecessary salvage therapy.
| S-EPMC8717050 | biostudies-literature