Malignant Transformation Of Low-grade Gliomas Research Articles

NCOG-38. UNDERSTANDING GLIOMA IN LI-FRAUMENI SYNDROME: HIGHLIGHTING THE VALUE OF SCREENING AND GENE SEQUENCING

Abstract Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant disorder characterized by a germline mutation in the TP53 gene that confers an increased risk of developing cancers, including brain tumors. There is continued need to understand how LFS diagnosis impacts clinical management and outcomes of gliomas. We report the clinical course of two patients from our Neuro-Oncology. Patient 1 is a male who was diagnosed with a low-grade astrocytoma, IDH1 mutant at age 20 status post gross total resection. Given radiographic concern for tumor progression, he underwent re-resection 8 years later. Pathology showed gliosis with TP53-mutant cells. Next-generation sequencing (NGS) was positive a germline TP53 mutation, consistent with LFS. He is currently in surveillance 12 years after diagnosis without need for radiation or chemotherapy. Patient 2 is a female who was diagnosed with glioblastoma, IDH wildtype, MGMT promoter unmethylated at age 40. She was asymptomatic at the time of diagnosis as the tumor was found during routine screening. She underwent gross total resection, radiation with concurrent and adjuvant temozolomide. She is now 5 years from last treatment without recurrence. These cases illustrate the clinical spectrum of glioma in LFS. Both patients have had prolonged periods of survival without progression, even accounting for respective tumor type. Patient 1 was only diagnosed with LFS after radiographic concerns for progression. Using NGS to diagnosis LFS was clinically important, as previous reports have shown greater propensity for malignant transformation of low-grade glioma in LFS. Patient 2 was diagnosed with glioblastoma during screening and has had no recurrence. This highlights the value of early diagnosis and treatment of gliomas in patients with LFS, even if asymptomatic at discovery. Further research is needed to understand the clinical spectrum of glioma in LFS and to optimize the care of this unique patient population.

ALTERNATIVE LENGTHENING OF TELOMERES (ALT) IS SEEN IN A PROPORTION OF OLIGODENDROGLIOMAS AND IT IS ASSOCIATED WITH A WORSE PROGNOSIS

Abstract AIMS Oligodendrogliomas are well known to be mutated for TERTp, which is enigmatically a diagnostic criteria for molecular glioblastoma by WHO2021. It is generally believed that gliomas that are TERTp negative maintain their telomere lengths by means of Alternative Lengthening of Telomeres (ALT) which is usually reflected by mutations of ATRX. Oligodendrogliomas are known to be non-mutated for ATRX unlike astrocytomas. TERT re-arrangement has also been shown to be an alternative way of TERT activation. METHOD We evaluated 112 oligodendrogliomas of both Grades 2 (n=87) and 3 (n=25) (all IDH-mutant, 1p19q co-deleted and 93% TERTp mutated by Sanger sequencing) by FISH for ALT, MYC, PDGFRA, EGFR , CDKN2A HD, and +7/-10, the latter events being associated with malignant transformation in low-grade gliomas. RESULTS 40 cases (35.7%) showed ALT and ALT positivity was associated with worse PFS (p=.024) and remained an in- dependent prognosticator in multivariate analysis. Amplification was found in MYC (6.3%), PDGFRA (10.7%), EGFR (0.8%), CDKN2A HD (6.25%) and +7/-10 (0%) and they had no prognostic significance, likely due to low occurrences. ALT was found to be associated with MYC amplification (p=.004). ALT-positive cases were further evaluated by FISH for TERT re-arrangement, and targeted panel DNA sequencing. CIC mutation (62.1%) was as- sociated with shorter OS in Grade 2 tumours (p=.023) and was the only significant finding from panel sequencing. TERT re-arrangement was only seen in 10.7% and had no prognostic significance. CONCLUSIONS ALT is seen in a proportion of oligodendrogliomas in spite of TERTp mutations and is associated with a worse prognosis.

Retracted: Analysis of Clinical Characteristics and Risk Factors of Postoperative Recurrence and Malignant Transformation of Low-Grade Glioma.

[This retracts the article DOI: 10.1155/2022/4948943.].

Refining the Intraoperative Identification of Suspected High-Grade Glioma Using a Surgical Fluorescence Biomarker: GALA BIDD Study Report.

Improving intraoperative accuracy with a validated surgical biomarker is important because identifying high-grade areas within a glioma will aid neurosurgical decision-making and sampling. We designed a multicentre, prospective surgical cohort study (GALA-BIDD) to validate the presence of visible fluorescence as a pragmatic intraoperative surgical biomarker of suspected high-grade disease within a tumour mass in patients undergoing 5-aminolevulinic acid (5-ALA) fluorescence-guided cytoreductive surgery. A total of 106 patients with a suspected high-grade glioma or malignant transformation of a low-grade glioma were enrolled. Among the 99 patients who received 5-ALA, 89 patients were eligible to assess the correlation of fluorescence with diagnosis as per protocol. Of these 89, 81 patients had visible fluorescence at surgery, and 8 patients had no fluorescence. A total of 80 out of 81 fluorescent patients were diagnosed as high-grade gliomas on postoperative central review with 1 low-grade glioma case. Among the eight patients given 5-ALA who did not show any visible fluorescence, none were high-grade gliomas, and all were low-grade gliomas. Of the seven patients suspected radiologically of malignant transformation of low-grade gliomas and with visible fluorescence at surgery, six were diagnosed with high-grade gliomas, and one had no tissue collected. In patients where there is clinical suspicion, visible 5-ALA fluorescence has clinical utility as an intraoperative surgical biomarker of high-grade gliomas and can aid surgical decision-making and sampling. Further studies assessing the use of 5-ALA to assess malignant transformation in all diffuse gliomas may be valuable.

Analysis of Clinical Characteristics and Risk Factors of Postoperative Recurrence and Malignant Transformation of Low-Grade Glioma.

This research was developed to explore the clinical characteristics and related risk factors of postoperative recurrence and malignant transformation of low-grade glioma (LGG). The subjects were rolled into observation group (19 cases) and control group (51 cases) according to recurrence and malignant transformation during the follow-up period. The clinical data of the two groups were compared, and the risk factors of recurrence and malignant transformation were analyzed with the time of recurrence and malignant transformation as independent variables. The experimental results showed that the proportion of patients aged over 45 years in the observation group (63.16%) was higher than that in the control group (50.98%). The proportion of preoperative functional status score (KPS) ≥80 in the observation group (68.42%) was lower than that in the control group (78.43%). The proportion of patients with tumor over 5 cm in the control group (27.45%) was lower than that in the observation group (52.63%), and the proportion of total resection of tumor in the control group (47.06%) was higher than that in the observation group (21.05%). Furthermore, the multivariate analysis showed that preoperative KPS score, preoperative duration of disease, resection scope, postoperative treatment, oncotesticular antigen (OY-TES-1) mRNA, P53, mouse double microbody amplification gene (MDM2), vascular endothelial growth factor (VEGF), and epidermal growth factor receptor (EGFR) were independent risk factors (all P < 0.05). In summary, patients with postoperative recurrence and malignant transformation had poorer physical condition and higher degree of malignancy before surgery. Preoperative KPS score, duration of disease, surgical resection scope, postoperative treatment, OY-TES-1 mRNA, P53, MDM2, VEGF, and EGFR were the risk factors.

Prediction of Malignant Transformation of WHO II Astrocytoma Using Mathematical Models Incorporating Apparent Diffusion Coefficient and Contrast Enhancement.

Using only increasing contrast enhancement as a marker of malignant transformation (MT) in gliomas has low specificity and may affect interpretation of clinical outcomes. Therefore we developed a mathematical model to predict MT of low-grade gliomas (LGGs) by considering areas of reduced apparent diffusion coefficient (ADC) with increased contrast enhancement. Patients with contrast-enhancing LGGs who had contemporaneous ADC and histopathology were retrospectively analyzed. Multiple clinical factors and imaging factors (contrast-enhancement size, whole-tumor size, and ADC) were assessed for association with MT. Patients were split into training and validation groups for the development of a predictive model using logistic regression which was assessed with receiver operating characteristic analysis. Among 132 patients, (median age 46.5 years), 106 patients (64 MT) were assigned to the training group and 26 (20 MT) to the validation group. The predictive model comprised age (P = 0.110), radiotherapy (P = 0.168), contrast-enhancement size (P = 0.015), and ADC (P < 0.001). The predictive model (area-under-the-curve [AUC] 0.87) outperformed ADC (AUC 0.85) and contrast-enhancement size (AUC 0.67). The model had an accuracy of 84% for the training group and 85% respectively for the validation group. Our model incorporating ADC and contrast-enhancement size predicted MT in contrast-enhancing LGGs.

Role and value of inflammatory markers in brain tumors: A case controlled study

IntroductionBrain tumor is one of the most devastating diseases in the world. The Pathogenesis is vary in multiple aspect of mechanism. The tumor microenvironment contains many different noncancerous cell types in addition to cancer cells. Inflammation is thought to be one of the factors that influence the oncogenesis process in brain tumors. MethodsThis study is a case controlled analytical study that analyzes the relationship between levels of inflammatory markers with the type of brain tumor. Samples of 35 people were then categorized according to the variables above and analyzing to measure its significance. ResultsBased on demografic study, most sample was male with age was 41–50 years It was found that high levels of procalcitonin were found in the case of glioma brain tumors. Procalcitonin level was considered a significant marker in predicting the severity of a brain tumor (p < 0.005). There was no significant value between the C-Reactive Protein and Neutrophyl-Lymphocyte ratio values for brain tumors. DiscussionAbnormal inflammation is a characteristic of malignant cancers and malignant transformation of low-grade gliomas and other brain tumor. Inflammation-induced activation of transcription factors contributes to the survival and rapid growth of glioma cells. ConclusionAs in other malignant cancers, inflammation may contribute to tumor progression. Biomarkers based on inflammation, such as the classical example of Procalcitonin and C-reactive protein, have been used to assess prognosis of glioma patients. These results should be validated and extended in larger clinical studies.

Systematic review-Time to malignant transformation in low-grade gliomas: Predicting a catastrophic event with clinical, neuroimaging, and molecular markers.

BackgroundDespite an initially indolent course, all WHO grade II, LGGs inevitably transform to malignant, WHO grades III and IV, without current curative options. Malignant transformation (MT) remains unpredictable with limited prognostic markers to steer timing of interventions. The aim of this study was to review and assign predictive value to specific clinical, molecular, and radiological markers impacting MT, thereby justifying timely therapeutic interventions.MethodsSearches of MEDLINE, Embase, and Cochrane databases were conducted from inception to April 28, 2021 and outputs were analysed in accordance with PRISMA protocol.ResultsFrom an initial 5,032 articles, 33 articles were included, totalling 5672 patients. Forty-three prognostic factors were registered to significantly impact MT. These were categorised as 7 clinical; 14 neuroimaging; 8 biological/molecular; 3 volumetric; 5 topological; 3 histological; and 3 treatment-related. Following analysis, 10 factors were highlighted: the pre-operative prognosticators were 1. presentation with epileptic seizures; 2. VDE > 8 mm/y; 3. VDE > 4 mm/y; 4. rCBV > 1.75; 5. PTV ≥ 5 cm (65 ml); 6. PTV ≥ 100 ml; and 7. cortical involvement. The post-operative prognosticators were: (1) IDH-wt, (2) TP53 mutation, and (3) temozolomide monotherapy.ConclusionsThe management of LGGs remains controversial, as conservative and invasive treatment may be associated with MT and impaired quality of life, respectively. Our review indicates that MT can be predicted by specific metrics in VDE, PTV, and rCBV, alongside cortical involvement. Additionally, patients with IDH-wt tumours TP53 mutations, or receiving TMZ monotherapy are more likely to undergo MT. Our data may form the basis of a predictive scoring system.

Role of Adamts-1 in Pleomorphic Xanthoastrocytoma Tumor Cells Progression.

To analyze the expression of ADAMTS-1, NF-?B, and STAT3 in human pleomorphic xanthoastrocytoma specimens, and their correlation with glioma advancement. Pleomorphic xanthoastrocytoma tumor cell lines were treated with low and high doses of cytokines at 24 and 48 hours (h) to replicate the inflammatory environment. The effects of IL-1 were assessed with the scratch wound-healing assay, and the expression levels of ADAMTS-1, NF-?B, and STAT3 of the groups were determined by western blot analysis. Cytokine treatment significantly increased the migration of PXA glioma cells after scratching at 24h and 48h time points. Similarly, 10 and 30 ng/mL IL-1 induced 1.86 and 1.94 fold increases, respectively, in ADAMTS-1 expression after 24h, and 3 and 3.27 fold increases, respectively, after 48h, compared with the non-treatment control group.10 and 30 ng/mL IL-1 doses caused 2.5 and 2.6 fold increase, in NF-?B protein levels after 24h, and 3.16 and 3.41 fold increases after 48h, compared with the non-treatment group. The protein levels of STAT3 after 24h were 2.62 and 2.43 fold higher, and 3.78 and 3.84 fold higher after 48 hours, with 10 and 30 ng/mL IL-1, compared with the non-treatment group. The proliferation and progression of glioma cells were proportional to the increased expression levels of ADAMTS-1, NF-?B, and STAT3. Our findings indicate that the proteolytic function of ADAMTS-1 may be associated with the malignant transformation of low-grade gliomas.

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

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.

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

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

MRS as an Aid to Diagnose Malignant Transformation in Low-Grade Gliomas with Increasing Contrast Enhancement.

Increased contrast enhancement has been used as a marker of malignant transformation in low-grade gliomas. This marker has been found to have limited accuracy because many low-grade gliomas with increased contrast enhancement remain grade II. We aimed to investigate whether MR spectroscopy can contribute to the diagnosis of malignant transformation in low-grade gliomas with increased contrast enhancement. Patients with low-grade gliomas who had contemporaneous MR spectroscopy and histopathology for tumor regions with increased contrast enhancement between 2004 and 2015 were retrospectively reviewed. Clinical data collected were sex and age, Karnofsky Performance Scale, histologic subtypes, isocitrate dehydrogenase 1 mutation status, disease duration, adjuvant therapy, and post-radiation therapy duration. Imaging data collected were contrast-enhancement size, whole-tumor size, MR spectroscopy metabolite ratios, and tumor grades of regions with increased contrast enhancement. Diagnostic values of these factors on malignant transformation of low-grade gliomas were statistically analyzed. A total of 86 patients with 96 MR spectroscopy studies were included. Tumor grades associated with increased contrast enhancement were grade II (n = 42), grade III (n = 27), and grade IV (n = 27). On multivariate analysis, the NAA/Cho ratio was the only significant factor (P < .001; OR, 7.1; 95% CI, 3.2-16.1) diagnostic of malignant transformation. With 0.222 as the cutoff value, the sensitivity, specificity, and accuracy of NAA/Cho for diagnosing malignant transformation were 94.4%, 83.3%, and 89.6%, respectively. MR spectroscopy complements conventional MR imaging in the diagnosis of malignant transformation in a subgroup of low-grade gliomas with increased contrast enhancement.

Role of CX3CR1 signaling in malignant transformation of gliomas.

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. 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. 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. 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.

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

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.

Identification of 3 subpopulations of tumor-infiltrating immune cells for malignant transformation of low-grade glioma

BackgroundTumor-infiltrating immune cells (TIICs) are highly relevant to clinical outcome of glioma. However, previous studies cannot account for the diverse functions that make up the immune response in malignant transformation (MT) from low-grade glioma (LGG) to high-grade glioma (HGG).MethodsTranscriptome level, genomic profiles and its relationship with clinical practice were obtained from TCGA and CGGA database. The “Cell type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT)” algorithm was used to estimate the fraction of 22 immune cell types. We divided the TCGA and CGGA set into an experiment set (n = 174) and a validation set (n = 74) by random number table method. Univariate and multivariate analyses were performed to evaluate the 22 TIICs’ value for MT in LGG. ROC curve was plotted to calculate area under curve (AUC) and cut-off value.ResultsHeterogeneity between TIICs exists in both intra- and inter-groups. Several TIICs are notably associated with tumor grade, molecular subtypes and survival. T follicular helper (TFH) cells, activated NK Cells and M0 macrophages were screened out to be independent predictors for MT in LGG and formed an immune risk score (IRS) (AUC = 0.732, p < 0.001, 95% CI 0.657–0.808 cut-off value = 0.191). In addition, the IRS model was validated by validation group, Immunohistochemistry (IHC) and functional enrichment analyses.ConclusionsThe proposed IRS model provides promising novel signatures for predicting MT from LGG to HGG and may bring a better design of glioma immunotherapy studies in years to come.

Role of CX3CR1 Signaling in Malignant Transformation of Gliomas

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.

Texture analysis on conventional MRI images accurately predicts early malignant transformation of low-grade gliomas.

Texture analysis performed on MRI images can provide additional quantitative information that is invisible to human assessment. This study aimed to evaluate the feasibility of texture analysis on preoperative conventional MRI images in predicting early malignant transformation from low- to high-grade glioma and compare its utility to histogram analysis alone. A total of 68 patients with low-grade glioma (LGG) were included in this study, 15 of which showed malignant transformation. Patients were randomly divided into training (60%) and testing (40%) sets. Texture analyses were performed to obtain the most discriminant factor (MDF) values for both training and testing data. Receiver operating characteristic (ROC) curve analyses were performed on MDF values and 9 histogram parameters in the training data to obtain cutoff values for determining the correct rates of discrimination between two groups in the testing data. The ROC analyses on MDF values resulted in an area under the curve (AUC) of 0.90 (sensitivity 85%, specificity 84%) for T2w FLAIR, 0.92 (86%, 94%) for ADC, 0.96 (97%, 84%) for T1w, and 0.82 (78%, 75%) for T1w + Gd and correctly discriminated between the two groups in 93%, 100%, 93%, and 92% of cases in testing data, respectively. In the astrocytoma subgroup, AUCs were 0.92 (88%, 83%) for T2w FLAIR and 0.90 (92%, 74%) for T1w + Gd and correctly discriminated two groups in 100% and 92% of cases. The MDF outperformed all 9 of the histogram parameters. Texture analysis on conventional preoperative MRI images can accurately predict early malignant transformation of LGGs, which may guide therapeutic planning. • Texture analysis performed on MRI images can provide additional quantitative information that is invisible to human assessment. • Texture analysis based on conventional preoperative MR images can accurately predict early malignant transformation from low- to high-grade glioma. • Texture analysis is a clinically feasible technique that may provide an alternative and effective way of determining the likelihood of early malignant transformation and help guide therapeutic decisions.

The diagnostic accuracy of detecting malignant transformation of low-grade glioma using O-(2-[18F]fluoroethyl)-l-tyrosine positron emission tomography: a retrospective study.

The diagnostic accuracy of O-(2-[18F]fluoroethyl)-l-tyrosine (FET) PET scanning in detecting the malignant transformation of low-grade gliomas (LGGs) is controversial. In this study, the authors retrospectively assessed the diagnostic potential of FET PET in patients with MRI-suspected malignant progression of LGGs that had previously been treated and the relationship between FET uptake and MRI and molecular biomarkers. Forty-two patients who had previously undergone surgical or multimodal treatment for a histologically verified LGG were referred for FET PET assessment because of clinical signs and/or MRI findings suggestive of tumor progression. Maximal and mean tumor-to-brain ratios (TBRmax and TBRmean, respectively) on FET PET as well as kinetic FET PET parameters (time to peak [TTP] and time-activity curve [TAC]) were determined. Final diagnoses were confirmed histologically. The diagnostic accuracy of FET parameters, separately and combined, for the detection of malignant progression was evaluated using receiver operating characteristic (ROC) curve analysis. Possible predictors that might influence the diagnostic accuracy of FET PET were assessed using multiple linear regression analysis. Spearman’s rank correlation r method was applied to determine the correlation between TBRmax and TAC, and molecular biomarkers from tumor tissues. A total of 47 FET PET scans were obtained and showed no significant association between FET parameters and contrast enhancement on MRI. ROC curve analyses overall were unable to demonstrate any significant differentiation between nontransformed LGGs and LGGs that had transformed to high-grade gliomas when evaluating FET parameters separately or combined. After excluding the oligodendroglial subgroup, a significant difference was observed between nontransformed and transformed LGGs when combining FET parameters (i.e., TBRmax > 1.6, TAC describing a plateau or decreasing pattern, and TTP < 25 minutes), with the best result yielded by a combined analysis of TBRmax > 1.6 and TAC with a plateau or decreasing pattern (sensitivity 75% and specificity 83%, p = 0.003). The difference was even greater when patients who had previously undergone oncological treatment were also excluded (sensitivity 93% and specificity 100%, p = 0.001). Multiple linear regression analysis revealed that the presence of an oligodendroglial component (p = 0.029), previous oncological treatment (p = 0.039), and the combined FET parameters (p = 0.027) were significant confounding factors in the detection of malignant progression. TBRmax was positively correlated with increasing cell density (p = 0.040) and inversely correlated with IDH1 mutation (p = 0.006). A single FET PET scan obtained at the time of radiological and/or clinical progression seems to be of limited value in distinguishing transformed from nontransformed LGGs, especially if knowledge of the primary tumor histopathology is not known. Therefore, FET PET imaging alone is not adequate to replace histological confirmation, but it may provide valuable information on the location and delineation of active tumor tissue, as well as an assessment of tumor biology in a subgroup of LGGs.

Non-standard radiotherapy fractionations delay the time to malignant transformation of low-grade gliomas.

Grade II gliomas are slowly growing primary brain tumors that affect mostly young patients. Cytotoxic therapies (radiotherapy and/or chemotherapy) are used initially only for patients having a bad prognosis. These therapies are planned following the “maximum dose in minimum time” principle, i. e. the same schedule used for high-grade brain tumors in spite of their very different behavior. These tumors transform after a variable time into high-grade gliomas, which significantly decreases the patient’s life expectancy. In this paper we study mathematical models describing the growth of grade II gliomas in response to radiotherapy. We find that protracted metronomic fractionations, i.e. therapeutical schedules enlarging the time interval between low-dose radiotherapy fractions, may lead to a better tumor control without an increase in toxicity. Other non-standard fractionations such as protracted or hypoprotracted schemes may also be beneficial. The potential survival improvement depends on the tumor’s proliferation rate and can be even of the order of years. A conservative metronomic scheme, still being a suboptimal treatment, delays the time to malignant progression by at least one year when compared to the standard scheme.

Malignant transformation of low-grade gliomas in patients undergoing adjuvant therapy.

Low-grade gliomas (LGG) comprise nearly 15-20% of all central nervous system glial tumors. Several factors have been recognized as playing role in LGG malignant transformation (MT). A breakthrough analysis of a multidisciplinary group pointed that temozolomide may play a role in MT of LGGs. We analyzed the prevalence of MT in LGG patients submitted to adjuvant therapy (AT). We analyzed the medical charts of 43 patients with LGG submitted to surgery or biopsy and attending at Hospital do Servidor Público Estadual de São Paulo (São Paulo, Brazil), consecutively diagnosed from 1995 to 2013. 43 patients (24 women and 19 men) were evaluated, with mean age of 45.3years. According to histology, 30 were astrocytomas (70%), 12 (27%) were oligodendrogliomas, and 1 (3%) were mixed glioma. Mean follow-up time was 4.2years with the standard deviation of 2.1. Twenty-eight patients did not receive adjuvant therapy and 15 received adjuvant therapy. From 43 patients with complete follow-up, 21 (48%) experienced malignant transformation. Among such patients, nine were users of AT. Forty-eight percent of patients presented MT, being 60% in the AT group and 42.8% without AT. Our analysis revealed a high prevalence of MT in patients undergoing AT, higher than in patients without AT.