scholarly journals Relevance of Dynamic 18F-DOPA PET Radiomics for Differentiation of High-Grade Glioma Progression from Treatment-Related Changes

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1924
Author(s):  
Shamimeh Ahrari ◽  
Timothée Zaragori ◽  
Laura Rozenblum ◽  
Julien Oster ◽  
Laëtitia Imbert ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Reference Model ◽  
External Validation ◽  
Standard Of Care ◽  
High Grade Glioma ◽  
High Grade ◽  
Parametric Images ◽  
Time To Peak ◽  
Additional Value ◽  
Glioma Progression

This study evaluates the relevance of 18F-DOPA PET static and dynamic radiomics for differentiation of high-grade glioma (HGG) progression from treatment-related changes (TRC) by comparing diagnostic performances to the current PET imaging standard of care. Eighty-five patients with histologically confirmed HGG and investigated by dynamic 18F-FDOPA PET in two institutions were retrospectively selected. ElasticNet logistic regression, Random Forest and XGBoost machine models were trained with different sets of features—radiomics extracted from static tumor-to-background-ratio (TBR) parametric images, radiomics extracted from time-to-peak (TTP) parametric images, as well as combination of both—in order to discriminate glioma progression from TRC at 6 months from the PET scan. Diagnostic performances of the models were compared to a logistic regression model with TBRmean ± clinical features used as reference. Training was performed on data from the first center, while external validation was performed on data from the second center. Best radiomics models showed only slightly better performances than the reference model (respective AUCs of 0.834 vs. 0.792, p < 0.001). Our current results show similar findings at the multicentric level using different machine learning models and report a marginal additional value for TBR static and TTP dynamic radiomics over the classical analysis based on TBR values.

scholarly journals Biological intratumoral therapy for the high-grade glioma part I: intratumoral delivery and immunotoxins

CNS Oncology ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. CNS38 ◽  
Author(s):  
Joshua Loya ◽  
Charlie Zhang ◽  
Emily Cox ◽  
Achal S Achrol ◽  
Santosh Kesari
Keyword(s):  
Translational Research ◽  
Standard Of Care ◽  
High Grade Glioma ◽  
Therapeutic Strategies ◽  
High Grade ◽  
Major Focus ◽  
Microsurgical Resection ◽  
Intratumoral Delivery ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic

Management of high-grade gliomas remains a complex challenge. Standard of care consists of microsurgical resection, chemotherapy and radiation, but despite these aggressive multimodality therapies the overall prognosis remains poor. A major focus of ongoing translational research studies is to develop novel therapeutic strategies that can maximize tumor cell eradication while minimizing collateral side effects. Particularly, biological intratumoral therapies have been the focus of new translational research efforts due to their inherent potential to be both dynamically adaptive and target specific. This two-part review will provide an overview of biological intratumoral therapies and summarize key advances and remaining challenges in intratumoral biological therapies for high-grade glioma. Part I focuses on discussion of the concepts of intratumoral delivery and immunotoxin therapies.

scholarly journals Cutting Edge Therapeutic Insights Derived from Molecular Biology of Pediatric High-Grade Glioma and Diffuse Intrinsic Pontine Glioma (DIPG)

2018 ◽  
Vol 5 (4) ◽  
pp. 88 ◽  
Author(s):  
Cavan Bailey ◽  
Mary Figueroa ◽  
Sana Mohiuddin ◽  
Wafik Zaky ◽  
Joya Chandra
Keyword(s):  
Clinical Trial Data ◽  
Standard Of Care ◽  
High Grade Glioma ◽  
Diffuse Intrinsic Pontine Glioma ◽  
High Grade ◽  
Pontine Glioma ◽  
Clinical Models ◽  
Malignant Glioma Cells ◽  
Epigenetic Disruption ◽  
Pediatric High Grade Glioma

Pediatric high-grade glioma (pHGG) and brainstem gliomas are some of the most challenging cancers to treat in children, with no effective therapies and 5-year survival at ~2% for diffuse intrinsic pontine glioma (DIPG) patients. The standard of care for pHGG as a whole remains surgery and radiation combined with chemotherapy, while radiation alone is standard treatment for DIPG. Unfortunately, these therapies lack specificity for malignant glioma cells and have few to no reliable biomarkers of efficacy. Recent discoveries have revealed that epigenetic disruption by highly conserved mutations in DNA-packaging histone proteins in pHGG, especially DIPG, contribute to the aggressive nature of these cancers. In this review we pose unanswered questions and address unexplored mechanisms in pre-clinical models and clinical trial data from pHGG patients. Particular focus will be paid towards therapeutics targeting chromatin modifiers and other epigenetic vulnerabilities that can be exploited for pHGG therapy. Further delineation of rational therapeutic combinations has strong potential to drive development of safe and efficacious treatments for pHGG patients.

scholarly journals NEIM-03. FEASIBILITY OF AUTOMATED ASSESSMENT OF PROGRESSIVE ENHANCEMENT ON MRI IN PATIENTS WITH NEWLY DIAGNOSED HIGH-GRADE GLIOMA USING A FEATURE-BASED ALGORITHM

2021 ◽  
Vol 3 (Supplement_4) ◽  
pp. iv7-iv7
Author(s):  
Daniel Barboriak ◽  
Katy Peters ◽  
Allan Friedman ◽  
Henry Friedman ◽  
Annick Desjardins
Keyword(s):  
Open Source ◽  
Tumor Imaging ◽  
Standard Of Care ◽  
High Grade Glioma ◽  
High Grade ◽  
Newly Diagnosed ◽  
Automated Identification ◽  
Imaging Protocol ◽  
Segmentation Algorithms ◽  
Feature Based

Abstract BACKGROUND Approximately 50% of patients with newly diagnosed high-grade glioma (HGG) develop progressive enhancement between their post-operative MRI scan and 12 weeks after radiation and temozolomide. Inter-reader variability on the assessment of progressive enhancement in this patient group is a significant barrier in designing multi-center biomarker trials to distinguish true progression from pseudoprogression. Although enhancement segmentation algorithms have become more widely available, more automated and reproducible techniques to identify patients who develop progressive enhancement are needed to facilitate acquisition of non-standard of care biomarkers when this occurs. We explored the feasibility of using a feature-based algorithm in tandem with freely available / open source automated segmentation algorithms to identify this subset of patients. METHODS An automated algorithm using subtraction of registered segmentations to detect new areas of localized thickness of enhancement was developed. Criteria for feasibility (50% within 95% CI of percent patients identified, and sensitivity of &gt;85% of patients assessed as progressed [P+] identified) were determined prospectively. The algorithm was implemented across five different automated enhancement segmentation techniques, then evaluated using a retrospective dataset of 73 patients with newly diagnosed HGG (age 50.8±13.2 years, 37 men, 36 women, 50 GBM, 23 Grade III). Standardized post-baseline brain tumor imaging protocol MR acquisitions were obtained on 1.5T and 3T scanners (GE and Siemens). On chart review, 53% of patients were assessed by neuroradiologists and/or neuro-oncologists as P+ (progression vs. pseudoprogression). RESULTS 50% was within the 95% CI of percent of patients identified for all five segmentation algorithms. Sensitivity was over 85% for three segmentation algorithms, with the MIC-DKFZ algorithm having highest sensitivity of 92%. For this algorithm, specificity was 77%, PPV was 81% and NPV was 90%. CONCLUSION A feature-based algorithm in tandem with open source segmentation algorithms showed preliminary feasibility for automated identification of patients with progressive enhancement.

CBIO-04. G-QUADRUPLEX STABILIZATION ENHANCES REPLICATION STRESS AND DNA DAMAGE IN ATRX-DEFICIENT HIGH-GRADE GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi27-vi28
Author(s):  
Sharvari Dharmaiah ◽  
Vasudev Tadimeti ◽  
Prit Benny Malgulwar ◽  
Christian Alvarez ◽  
Ahsan Farooqi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Molecular Mechanisms ◽  
Standard Of Care ◽  
High Grade Glioma ◽  
Replication Stress ◽  
High Grade ◽  
Loss Of Function ◽  
Enhanced Sensitivity ◽  
Alternative Lengthening ◽  
Dna Secondary Structures

Abstract Loss of function mutations in α-thalassaemia/mental retardation X-linked (ATRX) are a critical molecular hallmark for invariably fatal high-grade glioma (HGG). Mutational inactivation of histone chaperone ATRX leads to accumulations of abnormal DNA secondary structures known as G-quadruplexes (G4s), thereby inducing replication stress and DNA damage. As G4s arise at GC-rich regions (i.e., pericentromeric and telomeric regions), ATRX-deficiency alters genome-wide accessibility of chromatin, leads to transcriptional dysregulation, and induces alternative lengthening of telomeres (ALT). Our goal is to target ATRX deficiency through G4 stabilizers, which represent a class of novel small molecule compounds that selectively bind to and stabilize G4 structures. However, the genomic consequences and efficacy of this therapy for ATRX-deficient HGG are poorly understood. We therefore sought to evaluate the molecular mechanisms that drive selective lethality in patient-derived ATRX-deficient glioma stem cells (GSCs), following G4 stabilization. We found that ATRX-deficient GSCs demonstrate dose-dependent enhanced sensitivity to G4 stabilization, compared to ATRX-intact controls. Cell viability assays confirmed the specificity of our G4 stabilizer in comparison to other commonly used G4 stabilizers. Interestingly, G4 stabilization activated p53-independent apoptosis in ATRX-deficient GSCs. Furthermore, ATRX-deficient GSCs exhibit upregulated expression of both ATR and ATM pathways upon G4 stabilization, indicating enhanced replication stress and DNA damage via double-stranded breaks, respectively. Our preliminary findings suggest that ATR and ATM activation leads to the inhibition of transcription factor NF-κB, which in turn drives apoptosis. Lastly, our data indicate that G4 stabilization perturbs the ALT phenotype in ATRX-deficient GSCs, likely contributing to telomeric dysfunction. Taken together, these findings suggest that G4 stabilizers could synergize with ionizing radiation, the standard of care, as they are both DNA-damaging therapies. Our work defines mechanisms of action and efficacy of a novel therapeutic strategy for ATRX-deficient HGG, with strong implications for other ATRX-deficient cancers.

scholarly journals Radiotherapy versus combination radiotherapy-bevacizumab for the treatment of recurrent high-grade glioma: a systematic review

2021 ◽  
Author(s):  
Daniel P. Kulinich ◽  
John P. Sheppard ◽  
Thien Nguyen ◽  
Aditya M. Kondajji ◽  
Ansley Unterberger ◽  
...  
Keyword(s):  
Systematic Review ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
High Grade Glioma ◽  
Target Volume ◽  
Adult Brain ◽  
High Grade ◽  
Who Grade ◽  
Fractionated Radiotherapy ◽  
Meta Analyses

Abstract Background High-grade gliomas (HGG) comprise the most common primary adult brain cancers and universally recur. Combination of re-irradiation therapy (reRT) and bevacizumab (BVZ) therapy for recurrent HGG is common, but its reported efficacy is mixed. Objective To assess clinical outcomes after reRT ± BVZ in recurrent HGG patients receiving stereotactic radiosurgery (SRS), hypofractionated radiosurgery (HFSRT), or fully fractionated radiotherapy (FFRT). Methods We performed a systematic review of PubMed, Web of Science, Scopus, Embase, and Cochrane databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We identified studies reporting outcomes for patients with recurrent HGG treated via reRT ± BVZ. Cohorts were stratified by BVZ treatment status and re-irradiation modality (SRS, HFSRT, and FFRT). Outcome variables were overall survival (OS), progression-free survival (PFS), and radiation necrosis (RN). Results Data on 1399 patients was analyzed, with 954 patients receiving reRT alone and 445 patients receiving reRT + BVZ. All patients initially underwent standard-of-care therapy for their primary HGG. In a multivariate analysis that adjusted for median patient age, WHO grade, RT dosing, reRT fractionation regimen, time between primary and re-irradiation, and re-irradiation target volume, BVZ therapy was associated with significantly improved OS (2.51, 95% CI [0.11, 4.92] months, P = .041) but no significant improvement in PFS (1.40, 95% CI [− 0.36, 3.18] months, P = .099). Patients receiving BVZ also had significantly lower rates of RN (2.2% vs 6.5%, P < .001). Conclusions Combination of reRT + BVZ may improve OS and reduce RN rates in recurrent HGG, but further controlled studies are needed to confirm these effects.

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