Spatial distribution of malignant transformation in patients with low-grade glioma

Abstract Background Malignant transformation represents the natural evolution of diffuse low-grade gliomas (LGG). This is a catastrophic event, causing neurocognitive symptoms, intensified treatment and premature death. However, little is known concerning the spatial distribution of malignant transformation in patients with LGG. Materials and methods Patients histopathological diagnosed with LGG and subsequent radiological malignant transformation were identified from two different institutions. We evaluated the spatial distribution of malignant transformation with (1) visual inspection and (2) segmentations of longitudinal tumor volumes. In (1) a radiological transformation site < 2 cm from the tumor on preceding MRI was defined local transformation. In (2) overlap with pretreatment volume after importation into a common space was defined as local transformation. With a centroid model we explored if there were particular patterns of transformations within relevant subgroups. Results We included 43 patients in the clinical evaluation, and 36 patients had MRIs scans available for longitudinal segmentations. Prior to malignant transformation, residual radiological tumor volumes were > 10 ml in 93% of patients. The transformation site was considered local in 91% of patients by clinical assessment. Patients treated with radiotherapy prior to transformation had somewhat lower rate of local transformations (83%). Based upon the segmentations, the transformation was local in 92%. We did not observe any particular pattern of transformations in examined molecular subgroups. Conclusion Malignant transformation occurs locally and within the T2w hyperintensities in most patients. Although LGG is an infiltrating disease, this data conceptually strengthens the role of loco-regional treatments in patients with LGG.

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Exploring the role of inflammation in the malignant transformation of low-grade gliomas

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2016.05.019 ◽

2016 ◽

Vol 297 ◽

pp. 132-140 ◽

Cited By ~ 25

Author(s):

Nicole Michelson ◽

Jordina Rincon-Torroella ◽

Alfredo Quiñones-Hinojosa ◽

Jeffrey P. Greenfield

Keyword(s):

Malignant Transformation ◽

Low Grade ◽

Low Grade Gliomas

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Low-Grade Gliomas: Role of Relative Cerebral Blood Volume in Malignant Transformation

Tumors of the Central Nervous System, Volume 2 ◽

10.1007/978-94-007-0618-7_41 ◽

2011 ◽

pp. 417-423

Author(s):

Neil Upadhyay ◽

Adam D. Waldman

Keyword(s):

Malignant Transformation ◽

Blood Volume ◽

Cerebral Blood Volume ◽

Low Grade ◽

Low Grade Gliomas ◽

Relative Cerebral Blood Volume

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Role of CX3CR1 signaling in malignant transformation of gliomas

Neuro-Oncology ◽

10.1093/neuonc/noaa075 ◽

2020 ◽

Vol 22 (10) ◽

pp. 1463-1473 ◽

Cited By ~ 2

Author(s):

Sungho Lee ◽

Khatri Latha ◽

Ganiraju Manyam ◽

Yuhui Yang ◽

Arvind Rao ◽

...

Keyword(s):

Tumor Microenvironment ◽

Mouse Model ◽

Malignant Transformation ◽

Microvessel Density ◽

Progression Free Survival ◽

Macrophage Infiltration ◽

M2 Macrophage ◽

Low Grade ◽

Free Survival

Abstract Background Chemokine signaling may contribute to progression of low-grade gliomas (LGGs) by altering tumor behavior or impacting the tumor microenvironment. In this study, we investigated the role of CX3C chemokine receptor 1 (CX3CR1) signaling in malignant transformation of LGGs. Methods Ninety patients with LGGs were genotyped for the presence of common CX3CR1 V249I polymorphism and examined for genotype-dependent alterations in survival, gene expression, and tumor microenvironment. A genetically engineered mouse model was leveraged to model endogenous intracranial gliomas with targeted expression of CX3C ligand 1 (CX3CL1) and CX3CR1, individually or in combination. Results LGG patients who were heterozygous (V/I; n = 43) or homozygous (I/I; n = 2) for the CX3CR1 V249I polymorphism had significantly improved median overall (14.8 vs 9.8 y, P < 0.05) and progression-free survival (8.6 vs 6.5 y, P < 0.05) compared with those with the wild type genotype (V/V; n = 45). Tumors from the V/I + I/I group exhibited significantly decreased levels of CCL2 and MMP9 transcripts, correlating with reduced intratumoral M2 macrophage infiltration and microvessel density. In an immunocompetent mouse model of LGGs, coexpression of CX3CL1 and CX3CR1 promoted a more malignant tumor phenotype characterized by increased microglia/macrophage infiltration and microvessel density, resulting in shorter survival. Conclusions CX3CR1 V249I polymorphism is associated with improved overall and progression-free survival in LGGs. CX3CR1 signaling enhances accumulation of tumor associated microglia/macrophages and angiogenesis during malignant transformation.

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TMIC-61. ROLE OF CX3CR1 SIGNALING IN MALIGNANT TRANSFORMATION OF GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/noz175.1095 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi261-vi261

Author(s):

Sungho Lee ◽

Khatri Latha ◽

Ganesh Rao

Keyword(s):

Overall Survival ◽

Malignant Transformation ◽

Microvessel Density ◽

Median Overall Survival ◽

M2 Macrophage ◽

Low Grade ◽

M2 Macrophages ◽

Loss Of Function ◽

Altered Expression

Abstract High-grade gliomas (HGGs), including the most common primary brain tumor, glioblastoma (GBM), may arise from malignant transformation of low-grade gliomas (LGGs). While LGGs are often clinically indolent, GBMs have dismal outcomes despite maximal therapy. Accumulating data suggest that chemokine signaling directly contributes to malignant transformation of LGGs by altering tumor behavior or impacting the immune microenvironment. Here, we examined the role of CX3CR1 signaling in the malignant transformation of LGGs. First, patients with malignantly transformed LGGs were genotyped for the presence of the common loss-of-function CX3CR1 V249I polymorphism, and median overall survival was compared between the genotypes. Second, RNA sequencing data was analyzed for differential gene expression based on genotype. Third, surgical samples were examined for altered expression of M2 macrophage markers and microvessel density between the genotypes. Finally, a genetically-engineered murine model was leveraged to model endogenous intracranial gliomas with targeted expression of CX3CL1 and CX3CR1, individually or in combination. Our data demonstrate that heterozygosity (V/I) or homozygosity (I/I) for the loss-of-function CX3CR1 polymorphism was associated with significantly better median overall survival in patients with LGGs that have transformed to HGGs, compared to the wild type genotype (V/V). In addition, HGGs from V/I and I/I genotypes exhibit significantly decreased levels of CCL2, important for the recruitment of M2 macrophages, as well as decreased levels of ANGPT1 and MMP9, which mediate angiogenesis. This correlates with reduced intratumoral accumulation of CD204 positive macrophages and microvessel density in tumors from V/I and I/I patients. Finally, in the RCAS-PDGFB driven model of LGG, co-expression of CX3CL1 and CX3CR1 promotes more malignant tumor phenotype and shorter tumor-free survival. Taken together, our results show that CX3CR1 signaling promotes malignant transformation of LGGs via accumulation of glioma associated M2 macrophages and microglia and increased angiogenesis.

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The role of multi-parametric magnetic resonance imaging (MRI) in early prediction of malignant transformation of low-grade Gliomas (A Systematic review)

GSC Advanced Research and Reviews ◽

10.30574/gscarr.2020.5.3.0122 ◽

2020 ◽

Vol 5 (3) ◽

pp. 014-029

Author(s):

Mohammed Danfulani ◽

Shamsuddeen Ahmad Aliyu

Keyword(s):

Malignant Transformation ◽

Large Scale ◽

Reference List ◽

Low Grade ◽

Early Prediction ◽

High Tendency ◽

Hand Search ◽

Low Grade Gliomas ◽

Mri Studies

Introduction: Low-grade gliomas is the most common primary brain tumour, although the presentation may take up to two decades, there is high tendency of early malignant transformation which raise a growing concern. Multi-parametric MRI studies have the potential for predicting the early malignant transformation. Methods: A comprehensive electronic search of various databases was conducted together with forward tracking of the reference list to retrieve relevant qualitative primary studies. Moreover, hand search for journal that was not available electronically was also conducted. Through assessment of the relevant studies was ensured and the included studies were carefully selected. The relevant data was extracted by data extraction form recommended by Cochrane collaborations. Results: The search yielded 1158 which was narrowed down to eight (8) studies that satisfied the inclusion criteria. These studies are assessing the role of different MRI parameters in predicting the early malignant transformation of Low-grade gliomas. The risk of bias and the applicability concern of the included studies are low. Conclusion: Based on the findings of this review; Multi-parametric MRI studies have the potential of predicting the early malignant transformation of low-grade gliomas. There is need for high quality large scale, prospective studies on the role of multi-parametric MRI studies in early prediction of malignant transformation of LGGs and meta-analysis of these studies is highly recommended.

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Role of CX3CR1 Signaling in Malignant Transformation of Gliomas

Neurosurgery ◽

10.1093/neuros/nyz310_214 ◽

2019 ◽

Vol 66 (Supplement_1) ◽

Author(s):

Sungho Lee ◽

Khatri Latha ◽

Ganesh Rao

Keyword(s):

Overall Survival ◽

Malignant Transformation ◽

Microvessel Density ◽

Median Overall Survival ◽

M2 Macrophage ◽

Low Grade ◽

Loss Of Function ◽

Sequencing Data ◽

Altered Expression

Abstract INTRODUCTION High-grade gliomas (HGGs), including the most common primary brain tumor, glioblastoma (GBM), may arise from malignant transformation of low-grade gliomas (LGGs). While LGGs are often clinically indolent, GBMs have dismal outcomes despite maximal therapy. Accumulating evidence suggests that chemokine signaling directly contributes to malignant progression of LGGs by altering tumor behavior or impacting the immune microenvironment. Here, we examined the role of CX3CR1 signaling in malignant transformation of LGGs. METHODS First, patients with malignantly transformed LGGs were genotyped for the presence of the common loss-of-function CX3CR1 V249I polymorphism, and median overall survival was compared between the genotypes. Second, RNA sequencing data was analyzed for differential gene expression based on genotype. Third, surgical samples were examined for altered expression of M2 macrophage markers and microvessel density between the genotypes. Finally, genetically engineered murine model was leveraged to generate endogenous intracranial gliomas with targeted expression of CX3CL1 and CX3CR1, individually or in combination. RESULTS Heterozygosity (V/I) or homozygosity (I/I) for the loss-of-function CX3CR1 polymorphism is associated with significantly better median overall survival in patients with malignantly transformed LGGs, compared to the wild type genotype (V/V). In addition, HGGs from V/I and I/I genotypes exhibit significantly decreased levels of CCL2, important for the recruitment of M2 macrophages, as well as decreased levels of ANGPT1 and MMP9, which mediate angiogenesis. This correlates with reduced intratumoral accumulation of CD204-positive macrophages and microvessel density in tumors from V/I and I/I patients. Finally, in the RCAS-PDGFB driven model of LGG, co-expression of CX3CL1 and CX3CR1 promotes more malignant tumor phenotype and shorter tumor-free survival in association with increased intratumoral microglia and macrophage infiltration and microvessel density. CONCLUSION Taken together, our results show that CX3CL1-CX3CR1 signaling promotes malignant transformation of LGGs via accumulation of glioma associated macrophages and microglia and increased angiogenesis.

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