scholarly journals P04.10 IDH-wildtype low grade gliomas: overall survival and prognostic indicators

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii30-iii31
Author(s):  
G Berzero ◽  
A Di Stefano ◽  
S Ronchi ◽  
C Villa ◽  
Y Marie ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Overall Survival ◽  
Genetic Alterations ◽  
Biological Behavior ◽  
Low Grade ◽  
Rare Tumor ◽  
Who Grade ◽  
Grade Ii ◽  
Chromosome 9P ◽  
Who Grade Ii Gliomas

Abstract BACKGROUND IDH-wildtype WHO grade II diffuse gliomas represent a rare subgroup of low grade tumors characterized by poor prognosis. The clinical and molecular profile associated with these tumors has not been fully elucidated yet, and the ongoing uncertainties regarding their biological behavior hamper to establish a standard of treatment. The aim of this study is to define the median overall survival and the main prognostic factors associated with this rare tumor entity. MATERIALS AND METHODS We performed a retrospective research in our center for all patients diagnosed with diffuse WHO grade II and III gliomas from 1976 to 2018. WHO grade II and III gliomas were divided into three molecular subgroups according to the IDH1/2 mutation and the 1p/19q codeletion status (1: IDH-mutant, 1p/19q codeleted; 2: IDH-mutant, 1p/19q non codeleted; 3: IDH-wildtype). We analyzed the clinical and molecular characteristics of the three subgroups, and then the clinical, radiological, histological and molecular features of IDH-wildtype WHO grade II gliomas. RESULTS We identified 445 patients with diffuse WHO grade II gliomas, including 59 IDH1/2-wildtype tumors. IDH-wildtype grade II gliomas affected more frequently male (75% vs. 55%, p = 0.004) and older (mean age: 50.0 vs. 39.6 years, p<0.0001) patients, had frequent fronto-temporo-insular location (41%) and commonly underwent biopsy (53%) rather than resection. We found TERT promoter mutations (18/42, 43%), chromosome 7q gains (12/30, 40%), chromosome 10q losses (12/44, 27%), chromosome 9p losses (7/47, 15%), EGFR amplifications (5/51, 10%) and p16 deletions (4/50, 8%) but no P53 (0/16) mutations. Median overall survival was 46 months (vs. 98 for IDH-mutant non codeleted and 175 for IDH-mutant codeleted WHO grade II gliomas (p<0.0001); vs. 20 months for IDH-wildtype WHO grade III gliomas (p = 0.001)). Survival was not significantly influenced by age, preoperative KPS, tumor location, extent of resection or adjuvant treatment schemes. Chromosome 9p loss had a strong negative impact on overall survival (p=0.002). CONCLUSION The median overall survival associated with IDH-wildtype WHO grade II gliomas does not exceed 4 years from diagnosis. As some genetic alterations seem to have a strong prognostic impact, an exhaustive genetic assessment can be helpful in this rare tumor group for purposes of prognostic stratification and treatment decision.

scholarly journals BIOM-15. SUBVENTRICULAR ZONE INVOLVEMENT IS ASSOCIATED WITH WORSE OUTCOME IN GLIOMA WHO GRADE II INDEPENDENT OF MOLECULAR MARKERS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii4-ii5
Author(s):  
Philipp Karschnia ◽  
Jonathan Weller ◽  
Jens Blobner ◽  
Veit M Stoecklein ◽  
Mario M Dorostkar ◽  
...  
Keyword(s):  
Overall Survival ◽  
Molecular Markers ◽  
Subventricular Zone ◽  
Malignant Progression ◽  
Molecular Signature ◽  
Low Grade ◽  
First Line ◽  
Who Grade ◽  
Early Therapy ◽  
Grade Ii

Abstract BACKGROUND The subventricular zone represents a niche of adult neural stem cells. Involvement of the subventricular zone is associated with decreased survival in malignant glioma. We aimed to determine whether a similar association applies to low-grade gliomas. METHODS A retrospective institutional database search was performed for patients with glioma WHO grade II according to the 2016 classification. Demographic data, histology and molecular signature, imaging, and therapy were recorded and outcome was analysed for tumors with and without infiltration of the subventricular zone. RESULTS 182 patients with glioma WHO grade II were identified, including 97 oligodendrogliomas and 85 astrocytomas. 78 of 182 patients (43%) presented with subventricular zone involvement. Demographics, histopathology, and molecular signature did not differ between patients with and without subventricular zone involvement. First-line management included surgery, chemotherapy, radiotherapy, brachytherapy, and wait-and-scan approaches. Median follow-up was 43 months. Median time to malignant progression was 122 months; median overall survival was not reached. Subventricular zone involvement was a negative prognostic marker for time to malignant progression (p = 0.002) and overall survival (p = 0.023) in the entire cohort as well as in the subgroup of patients who were managed with wait-and-scan approaches. Among patients in which early therapy was provided, subventricular zone involvement was not prognostic for overall survival but for time to malignant progression. In multivariate analysis, subventricular zone involvement was associated with worse prognosis independent of molecular markers or treatment approaches including use of resection. CONCLUSION Subventricular zone involvement represents a key risk factor for worse outcome in glioma WHO grade II. Early first-line therapy may improve outcome in such patients.

scholarly journals Prognostic factors in low grade (WHO grade II) gliomas of the cerebral hemispheres: the role of surgery.

1996 ◽  
Vol 61 (3) ◽  
pp. 291-296 ◽  
Author(s):  
M Scerrati ◽  
R Roselli ◽  
M Iacoangeli ◽  
A Pompucci ◽  
G F Rossi
Keyword(s):  
Prognostic Factors ◽  
Cerebral Hemispheres ◽  
Low Grade ◽  
Who Grade ◽  
Grade Ii ◽  
Who Grade Ii Gliomas

390 The Impact of Extent of Resection on IDH1 Wild-Type or Mutant Low-Grade Gliomas

Neurosurgery ◽  
2017 ◽  
Vol 64 (CN_suppl_1) ◽  
pp. 293-294 ◽  
Author(s):  
Toral R Patel ◽  
Evan D Bander ◽  
Rachael A Venn ◽  
Tiffany L Powell Avila ◽  
Gustav Y Cederquist ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Cox Regression ◽  
Extent Of Resection ◽  
Low Grade ◽  
Wild Type ◽  
Who Grade ◽  
Cox Regression Analysis ◽  
Grade Ii ◽  
The Impact ◽  
Who Grade Ii Gliomas

Abstract INTRODUCTION Accumulating evidence suggests that maximizing extent of resection (EOR) improves outcomes for patients with WHO grade II low-grade gliomas (LGG). However, recent studies demonstrate that LGGs bearing a mutation in the isocitrate dehydrogenase 1 (IDH1) gene are a distinct molecular and clinical entity. It remains unclear whether maximizing EOR confers an equivalent clinical benefit in IDH mutated (mtIDH) and IDH wild-type (wtIDH) LGGs. To answer this question, we evaluated a cohort of patients with surgically-resection WHO grade II gliomas and known IDH1 mutation status, to assess the impact of EOR on malignant progression-free survival (MPFS) and overall survival (OS). METHODS We performed a retrospective review of 74 patients with WHO grade II gliomas and known IDH mutational status undergoing surgical resection at a single institution. EOR was assessed with quantitative three-dimensional volumetric analysis. The effect of predictor variables on MPFS and OS was analyzed with Cox regression models and the Kaplan-Meier method. RESULTS >52 (70%) mtIDH patients and 22 (30%) wtIDH patients were included. Median pre-operative tumor volume was 37.4 cm3 (range: 0.9-190.2 cm3). Median EOR was 57.6% (range: 0.08% 99.3%). Median follow-up was 44.4 months. Malignant progression was identified in 31 patients and 17 patients died. Univariate Cox regression analysis confirmed EOR as a prognostic factor for the entire cohort. However, Cox regression analysis stratified by IDH status demonstrated that a greater EOR independently prolonged MPFS and OS for wtIDH patients (HR = 0.002 [95% CI 0.000 - 0.074] and HR = 0.001 [95% CI 0.00 - 0.108], respectively), but not for mtIDH patients (HR = 0.84 [95% CI 0.17 - 4.13] and HR = 2.99 [95% CI 0.15 - 61.66], respectively). CONCLUSION Increasing EOR confers oncologic and survival benefits in IDH1 wild-type LGGs. However, the impact of EOR on IDH1 mutant LGGs is less significant and requires further study.

scholarly journals The molecular biology of WHO Grade II gliomas

2013 ◽  
Vol 34 (2) ◽  
pp. E1 ◽  
Author(s):  
Nicholas F. Marko ◽  
Robert J. Weil
Keyword(s):  
Molecular Biology ◽  
Tumor Biology ◽  
Molecular Characteristics ◽  
Low Grade ◽  
Diffuse Astrocytoma ◽  
Who Grade ◽  
Low Grade Gliomas ◽  
Molecular Features ◽  
Grade Ii ◽  
Who Grade Ii Gliomas

The WHO grading scheme for glial neoplasms assigns Grade II to 5 distinct tumors of astrocytic or oligodendroglial lineage: diffuse astrocytoma, oligodendroglioma, oligoastrocytoma, pleomorphic xanthoastrocytoma, and pilomyxoid astrocytoma. Although commonly referred to collectively as among the “low-grade gliomas,” these 5 tumors represent molecularly and clinically unique entities. Each is the subject of active basic research aimed at developing a more complete understanding of its molecular biology, and the pace of such research continues to accelerate. Additionally, because managing and predicting the course of these tumors has historically proven challenging, translational research regarding Grade II gliomas continues in the hopes of identifying novel molecular features that can better inform diagnostic, prognostic, and therapeutic strategies. Unfortunately, the basic and translational literature regarding the molecular biology of WHO Grade II gliomas remains nebulous. The authors' goal for this review was to present a comprehensive discussion of current knowledge regarding the molecular characteristics of these 5 WHO Grade II tumors on the chromosomal, genomic, and epigenomic levels. Additionally, they discuss the emerging evidence suggesting molecular differences between adult and pediatric Grade II gliomas. Finally, they present an overview of current strategies for using molecular data to classify low-grade gliomas into clinically relevant categories based on tumor biology.

Association between fluorine-18–labeled fluorodeoxyglucose uptake and 1p and 19q loss of heterozygosity in World Health Organization Grade II gliomas

2007 ◽  
Vol 106 (4) ◽  
pp. 633-637 ◽  
Author(s):  
Florian Stockhammer ◽  
Ulrich-Wilhelm Thomale ◽  
Michail Plotkin ◽  
Christian Hartmann ◽  
Andreas von Deimling
Keyword(s):  
World Health Organization ◽  
Fdg Pet ◽  
Magnetic Resonance Images ◽  
World Health ◽  
Low Grade ◽  
Who Grade ◽  
Fdg Uptake ◽  
Grade Ii ◽  
Health Organization ◽  
Who Grade Ii Gliomas

Object Oligodendroglial tumors harboring combined 1p and 19q loss (1p/19q LOH) are characterized by a favorable prognosis and response to chemotherapy and radiotherapy, but detection of 1p/19q LOH relies on postoperative procedures. The authors investigated the potential of fluorine-18–labeled fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) to predict 1p/19q LOH preoperatively in tumors whose appearance on initial magnetic resonance images was consistent with that of low-grade glioma. Methods The study population comprised 25 patients who had undergone preoperative FDG-PET followed by tumor resection. Neuronavigation ensured a precise match of FDG uptake wi th the site of biopsy. All tumor specimens were graded according to the World Health Organization (WHO) classification system. Microsatellite analysis was used to identify 1p/19q LOH. In this series, 16 of 25 gliomas corresponded to WHO Grade II. In eight of these 16, 1p/19q LOH was detected. Raised glucose utilization within the tumor was seen in the six of eight WHO Grade II gliomas with 1p/19q LOH and in none of the WHO Grade II gliomas without this genetic alteration (p = 0.003). Conclusions These findings demonstrate the potential of FDG-PET to predict 1p/19q LOH in WHO Grade II gliomas.

scholarly journals Influence of VEGF-A, VEGFR-1-3, and neuropilin 1-2 on progression-free: and overall survival in WHO grade II and III meningioma patients

2021 ◽  
Vol 52 (2) ◽  
pp. 233-243
Author(s):  
Simon Bernatz ◽  
Daniel Monden ◽  
Florian Gessler ◽  
Tijana Radic ◽  
Elke Hattingen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tumor Cells ◽  
Progression Free Survival ◽  
Staining Intensity ◽  
Who Grade ◽  
Positive Correlation ◽  
Protein Levels ◽  
Angiogenic Therapy ◽  
Neuropilin 1 ◽  
Grade Ii

AbstractHigher grade meningiomas tend to recur. We aimed to evaluate protein levels of vascular endothelial growth factor (VEGF)-A with the VEGF-receptors 1-3 and the co-receptors Neuropilin (NRP)-1 and -2 in WHO grade II and III meningiomas to elucidate the rationale for targeted treatments. We investigated 232 specimens of 147 patients suffering from cranial meningioma, including recurrent tumors. Immunohistochemistry for VEGF-A, VEGFR-1-3, and NRP-1/-2 was performed on tissue micro arrays. We applied a semiquantitative score (staining intensity x frequency). VEGF-A, VEGFR-1-3, and NRP-1 were heterogeneously expressed. NRP-2 was mainly absent. We demonstrated a significant increase of VEGF-A levels on tumor cells in WHO grade III meningiomas (p = 0.0098). We found a positive correlation between expression levels of VEGF-A and VEGFR-1 on tumor cells and vessels (p < 0.0001). In addition, there was a positive correlation of VEGF-A and VEGFR-3 expression on tumor vessels (p = 0.0034). VEGFR-2 expression was positively associated with progression-free survival (p = 0.0340). VEGF-A on tumor cells was negatively correlated with overall survival (p = 0.0084). The VEGF-A-driven system of tumor angiogenesis might still present a suitable target for adjuvant therapy in malignant meningioma disease. However, its role in malignant tumor progression may not be as crucial as expected. The value of comprehensive testing of the ligand and all receptors prior to administration of anti-angiogenic therapy needs to be evaluated in clinical trials.

scholarly journals RTID-05. INDIGO: A GLOBAL, RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY OF VORASIDENIB (AG-881) VS PLACEBO IN PATIENTS WITH RESIDUAL/RECURRENT GRADE II GLIOMA WITH AN ISOCITRATE DEHYDROGENASE 1/2 (IDH1/2) MUTATION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii194-ii194
Author(s):  
Ingo Mellinghoff ◽  
Martin van den Bent ◽  
Jennifer Clarke ◽  
Elizabeth Maher ◽  
Katherine Peters ◽  
...  
Keyword(s):  
High Risk ◽  
Dose Escalation ◽  
Objective Response ◽  
Data Monitoring Committee ◽  
Progression Free Survival ◽  
High Risk Population ◽  
Low Grade ◽  
Who Grade ◽  
Free Survival ◽  
Grade Ii

Abstract BACKGROUND Low-grade gliomas (LGGs; WHO grade II) are incurable and ultimately progress to high-grade gliomas. The current treatment options are surgery followed by observation (“watch and wait”) for patients with lower risk for disease progression or postoperative chemoradiotherapy (high-risk population). There are no approved targeted therapies. IDH1 and IDH2 mutations (mIDH1/2) occur in approximately 80% and 4% of LGGs, respectively, and promote tumorigenesis via neomorphic production of D-2-hydroxyglutarate. Vorasidenib, an oral, potent, reversible, brain-penetrant pan-inhibitor of mIDH1/2, was evaluated in 76 patients with glioma in two phase 1 studies (dose escalation and perioperative) and was associated with a favorable safety profile at daily doses below 100 mg. Preliminary clinical activity was observed in non-enhancing glioma patients in both studies, with an objective response rate (ORR) of 18.2% and median progression-free survival of 31.4 months in the dose escalation study. METHODS Approximately 366 patients will be randomized 1:1 to vorasidenib (50 mg QD) or matched placebo and stratified by 1p19q status (intact vs co-deleted). Key eligibility criteria: age ≥ 12 years; grade II oligodendroglioma or astrocytoma (per WHO 2016 criteria) not in need of immediate treatment and without high-risk features; centrally confirmed mIDH1/2 status; ≥ 1 surgery for glioma with most recent ≥ 1 year but ≤ 5 years before randomization, and no other anticancer therapy; Karnofsky performance status ≥ 80%; and centrally confirmed measurable, non-enhancing disease evaluable by magnetic resonance imaging. Crossover from placebo to the vorasidenib arm is permitted upon centrally confirmed radiographic progression per RANO-LGG criteria. Primary endpoint: progression-free survival assessed by independent review. Secondary endpoints: safety and tolerability, tumor growth rate assessed by volume, ORR, overall survival, and quality of life. Clinical data will be reviewed regularly by an independent data monitoring committee. The study is currently enrolling patients in the US, with additional countries planned (NCT04164901).

scholarly journals A 25-year retrospective, single center analysis of 343 WHO grade II/III glioma patients: implications for grading and temozolomide therapy

2021 ◽  
Author(s):  
Eike Steidl ◽  
Katharina Filipski ◽  
Pia S. Zeiner ◽  
Marlies Wagner ◽  
Emmanouil Fokas ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Molecular Markers ◽  
Treatment Time ◽  
Real Life ◽  
Patient Characteristics ◽  
Low Grade ◽  
Who Grade ◽  
Idh1 R132h ◽  
Treatment Data ◽  
Grade Ii

Abstract Purpose Classification and treatment of WHO grade II/III gliomas have dramatically changed. Implementing molecular markers into the WHO classification raised discussions about the significance of grading and clinical trials showed overall survival (OS) benefits for combined radiochemotherapy. As molecularly stratified treatment data outside clinical trials are scarce, we conducted this retrospective study. Methods We identified 343 patients (1995–2015) with newly diagnosed WHO grade II/III gliomas and analyzed molecular markers, patient characteristics, symptoms, histology, treatment, time to treatment failure (TTF) and OS. Results IDH-status was available for all patients (259 mutant, 84 IDH1-R132H-non-mutant). Molecular subclassification was possible in 173 tumors, resulting in diagnosis of 80 astrocytomas and 93 oligodendrogliomas. WHO grading remained significant for OS in astrocytomas/IDH1-R132H-non-mutant gliomas (p < 0.01) but not for oligodendroglioma (p = 0.27). Chemotherapy (and temozolomide in particular) showed inferior OS compared to radiotherapy in astrocytomas (median 6.1/12.1 years; p = 0.03) and oligodendrogliomas (median 13.2/not reached (n.r.) years; p = 0.03). While radiochemotherapy improved TTF in oligodendroglioma (median radiochemotherapy n.r./chemotherapy 3.8/radiotherapy 7.3 years; p < 0.001/ = 0.06; OS data immature) the effect, mainly in combination with temozolomide, was weaker in astrocytomas (median radiochemotherapy 6.7/chemotherapy 2.3/radiotherapy 2.0 years; p < 0.001/ = 0.11) and did not translate to improved OS (median 8.4 years). Conclusion This is one of the largest retrospective, real-life datasets reporting treatment and outcome in low-grade gliomas incorporating molecular markers. Current histologic grading features remain prognostic in astrocytomas while being insignificant in oligodendroglioma with interfering treatment effects. Chemotherapy (temozolomide) was less effective than radiotherapy in both astrocytomas and oligodendrogliomas while radiochemotherapy showed the highest TTF in oligodendrogliomas.

scholarly journals LGG-50. INTEGRATED MOLECULAR AND CLINICAL ANALYSIS OF 1,000 PEDIATRIC LOW-GRADE GLIOMAS UNCOVERS NOVEL SUBGROUPS FOR CLINICAL RISK STRATIFICATION

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii375-iii376
Author(s):  
Uri Tabori ◽  
Scott Ryall ◽  
Michal Zapotocky ◽  
Julie Bennett ◽  
Liana Nobre ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Clinical Presentation ◽  
Mapk Pathway ◽  
Clinical Analysis ◽  
Genetic Alterations ◽  
Low Grade ◽  
Who Grade ◽  
Low Grade Gliomas ◽  
Younger Age ◽  
Risk Categories

Abstract Pediatric low-grade gliomas (pLGG) are primarily driven by genetic alterations in the RAS/MAPK pathway, most commonly involving BRAF of NF1. Despite their molecular convergence, pLGG often show unexplained variability in their clinical outcome. To address this, we molecularly characterized a cohort of &gt;1,000 clinically annotated pLGG. 84% of cases harbored a detectable driver mutation. The remaining 16% of patients nonetheless showed RAS/MAPK pathway up-regulation at the RNA level. The clinical presentation and outcome of pLGG appeared highly variable and linked to the alteration type: re-arrangement or SNV. Re-arrangement-driven tumors were diagnosed at a younger age (6.6 versus 10.9 years, p&lt;0.0001), enriched for WHO grade I histology (88% versus 66%, p&lt;0.0001), infrequently progressed (27% versus 46%, p&lt;0.0001), and rarely resulted in death (3 versus 13%, p&lt;0.0001) as compared to SNV-driven tumors. These included the rarest molecular drivers of pLGG, for which we now have the clinicopathologic features of including MYB, MYBL1, FGFR2 fusions, FGFR1-TACC1, FGFR1 SNVs, IDH1 p.R132H, and H3.3 p.K27M. Utilizing this information, we suggest novel risk categories of pLGG that effectively predicted patient outcome. Low-risk tumors progressed infrequently and rarely succumbed to their disease (10-year PFS of 71% and OS of 98%). Intermediate-risk pLGG had a 10-year PFS and OS of 35% and 90%, respectively. High risk pLGG almost invariably progressed (10-year PFS of 0%) and these patients often succumbed to their disease (10-year OS of 41%). These data highlight the biological and clinical differences between pLGG subtypes and offers molecular based risk stratification to these cancers.

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