IDH wild-type WHO grade II diffuse low-grade gliomas. A heterogeneous family with different outcomes. Systematic review and meta-analysis

Abstract BACKGROUND Maximizing extent of resection (EOR) improves outcomes in adults with World Health Organization (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. OBJECTIVE To assess the impact of EOR on malignant progression-free survival (MPFS) and overall survival (OS) in mtIDH and wtIDH LGGs. METHODS We performed a retrospective review of 74 patients with WHO grade II gliomas and known IDH mutational status undergoing resection at a single institution. EOR was assessed with quantitative 3-dimensional volumetric analysis. The effect of predictor variables on MPFS and OS was analyzed with Cox regression models and the Kaplan–Meier method. RESULTS Fifty-two (70%) mtIDH patients and 22 (30%) wtIDH patients were included. Median preoperative tumor volume was 37.4 cm3; median EOR of 57.6% was achieved. Univariate Cox regression analysis confirmed EOR as a prognostic factor for the entire cohort. However, stratifying by IDH status demonstrates that greater EOR independently prolonged MPFS and OS for wtIDH patients (hazard ratio [HR] = 0.002 [95% confidence interval {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 wtLGGs, but the impact on IDH1 mtLGGs requires further study.

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Multicentric Registry Study on Epidemiological and Biological Disease Profile as Well as Clinical Outcome in Patients with Low-Grade Gliomas: The LoG-Glio Project

Journal of Neurological Surgery Part A Central European Neurosurgery ◽

10.1055/s-0039-1693650 ◽

2019 ◽

Vol 81 (01) ◽

pp. 048-057 ◽

Cited By ~ 1

Author(s):

Andrej Pala ◽

Minou Nadji-Ohl ◽

Katharina Faust ◽

Stefan Rückriegel ◽

Constantin Roder ◽

...

Keyword(s):

Surgical Management ◽

Adjuvant Treatment ◽

Low Grade ◽

Inclusion Criteria ◽

Wild Type ◽

Who Grade ◽

Low Grade Gliomas ◽

Grade Ii ◽

Multicenter Registry

Abstract Background World Health Organization (WHO) grade II low-grade gliomas (LGGs) in adults are rare, and patients' mean overall survival (OS) is relatively long. Epidemiological data on factors influencing tumor genesis and progression are scarce, and prospective data on surgical management are still lacking. Because of the molecular heterogeneity of LGG, a comprehensive molecular characterization is required for any clinical and epidemiological research. Further, a detailed radiologic assessment is needed as the only established objective criterion for progressive disease. Both radiologic and molecular assessments have to be standardized to produce comparable data. The aim of the registry is to improve the evidence for surgical management of LGG patients by establishing a multicenter registry with a strong surgical and clinical focus including mandatory biobanking. Methods The LoG-Glio project is a prospective national observational multicenter registry that began on November 1, 2015. Inclusion criteria encompass all patients > 18 years of age with a radiologic suspicion of LGG. Patients with severe neurologic or psychiatric disorders that may interfere with their informed consent or if there is no possibility for further follow-up are excluded. Diagnosis of glioblastoma WHO grade IV isocitrate dehydrogenase (IDH) wild type leads to a secondary exclusion of patients. In addition to demographic data, results of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, add-on for patients with brain tumors, and National Health Institute Stroke Scale before and after surgery and during regular follow-ups are collected. At each time point a detailed recording of surgical and adjuvant treatment is performed. Radiologic assessment involves three-dimensional (3D) acquisition of T1, fluid-attenuated inversion recovery, and T2 sequences. For the final evaluation, a central detailed neuropathologic and molecular assessment of tumor samples and a radiologic evaluation of imaging sets are part of the study protocol. Results We report the first 100 consecutively registered patients for LoG-Glio. Three patients dropped out due to loss of follow-up. Of the remaining recruited patients, 8 were classified as wait and scan; 89 had surgery. Using the inclusion criteria described previously, 70 patients had an IDH-mutated glioma, 10 had miscellaneous rare LGGs, and 8 patients had an IDH wild-type WHO grade II or III glioma. Conclusion The LoG-Glio registry has been successfully implemented. Applied selection criteria result in an appropriately balanced patient cohort. Short-term outcome data on epidemiology as well as the influence of current surgical techniques and adjuvant treatment on patient outcomes are expected. In the long run, the aim of the registry is to validate the new molecular-based WHO classification and the influence of the extent of resection on progression-free survival and OS. The registry provides an open platform for future research projects benefiting patients with LGG.

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The Role of Adjuvant Radiotherapy in Atypical (Who Grade II) Meningiomas: Meta-Analysis and Systematic Review of Literature

Journal of Neurological Surgery Part B Skull Base ◽

10.1055/s-0035-1546700 ◽

2015 ◽

Vol 76 (S 01) ◽

Cited By ~ 1

Author(s):

Maged Fam ◽

Sam Eljamel

Keyword(s):

Systematic Review ◽

Adjuvant Radiotherapy ◽

Meta Analysis ◽

Review Of Literature ◽

Who Grade ◽

Grade Ii

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Management of low-grade glioma: a systematic review and meta-analysis

Neuro-Oncology Practice ◽

10.1093/nop/npy034 ◽

2018 ◽

Vol 6 (4) ◽

pp. 249-258 ◽

Cited By ~ 7

Author(s):

Timothy J Brown ◽

Daniela A Bota ◽

Martin J van Den Bent ◽

Paul D Brown ◽

Elizabeth Maher ◽

...

Keyword(s):

Systematic Review ◽

Meta Analysis ◽

Progression Free Survival ◽

Low Grade Glioma ◽

World Health ◽

Subtotal Resection ◽

Low Grade ◽

Evidence Based ◽

Free Survival ◽

Low Grade Gliomas

Abstract Background Optimum management of low-grade gliomas remains controversial, and widespread practice variation exists. This evidence-based meta-analysis evaluates the association of extent of resection, radiation, and chemotherapy with mortality and progression-free survival at 2, 5, and 10 years in patients with low-grade glioma. Methods A quantitative systematic review was performed. Inclusion criteria included controlled trials of newly diagnosed low-grade (World Health Organization Grades I and II) gliomas in adults. Eligible studies were identified, assigned a level of evidence for every endpoint considered, and analyzed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The relative risk of mortality and of progression at 2, 5, and 10 years was calculated for patients undergoing resection (gross total, subtotal, or biopsy), radiation, or chemotherapy. Results Gross total resection was significantly associated with decreased mortality and likelihood of progression at all time points compared to subtotal resection. Early radiation was not associated with decreased mortality; however, progression-free survival was better at 5 years compared to patients receiving delayed or no radiation. Chemotherapy was associated with decreased mortality at 5 and 10 years in the high-quality literature. Progression-free survival was better at 5 and 10 years compared to patients who did not receive chemotherapy. In patients with isocitrate dehydrogenase 1 gene (IDH1) R132H mutations receiving chemotherapy, progression-free survival was better at 2 and 5 years than in patients with IDH1 wild-type gliomas. Conclusions Results from this review, the first to quantify differences in outcome associated with surgery, radiation, and chemotherapy in patients with low-grade gliomas, can be used to inform evidence-based management and future clinical trials.

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Interstitial radiosurgery of low-grade gliomas

Journal of Neurosurgery ◽

10.3171/jns.1995.82.3.0418 ◽

1995 ◽

Vol 82 (3) ◽

pp. 418-429 ◽

Cited By ~ 87

Author(s):

Friedrich W. Kreth ◽

Michael Faist ◽

Peter C. Warnke ◽

Reinhard Roβner ◽

Benedikt Volk ◽

...

Keyword(s):

Ct Scan ◽

Tumor Recurrence ◽

Survival Rates ◽

Low Grade ◽

Who Grade ◽

Content Type ◽

Low Grade Gliomas ◽

Interstitial Radiosurgery ◽

Grade Ii ◽

Fine Print

✓ The treatment of patients with low-grade gliomas remains a subject of controversy, especially with respect to new treatment modalities such as interstitial radiosurgery (brachytherapy), radiosurgery, and stereotactic radiotherapy. In a retrospective analysis conducted between 1979 and 1991, the authors studied the results of interstitial radiosurgery in 455 patients with low-grade gliomas (World Health Organization (WHO) Grade I + WHO Grade II) with regard to survival time, quality of life, the risk of malignant transformation, and the risk profile of the treatment concept. Interstitial radiosurgery with iodine-125 was performed using permanent (1979–1985) or temporary implants (after 1985) with low-dose rates (≤ 10 cGy/hr) and a reference dose of 60 to 100 Gy calculated to the outer rim of the tumor. The 5- and 10-year survival rates in patients with pilocytic astrocytomas (97 patients) were 84.9% and 83%, and in patients with WHO Grade II astrocytomas (250 patients) 61% and 51%, respectively. Five-year survival rates for patients with oligoastrocytomas (60 patients), oligodendrogliomas (27 patients), and gemistocytic astrocytomas (21 patients) were 49%, 50%, and 32%, respectively. In the group with WHO Grade II gliomas, young age and a good performance status were associated with a better prognosis. Unfavorable factors were midline shift, enhancement on computerized tomography (CT) scan, and tumor recurrence after previous radiotherapy or surgery. Tumor location had no influence on the prognosis (247 patients in this series had deep-seated tumors). Malignant transformation was the major cause of death. Important risk factors for malignancy were the patient's age, tumor enhancement in CT scan, and tumor recurrence after previous surgery or radiotherapy. Perioperative mortality was 0.9% and perioperative morbidity was 1.7%. Radiogenic complications were observed in 2.7% of all patients, most often in larger tumors and after using permanent implants. The authors conclude that interstitial radiosurgery represents a specific treatment modality for selected patients with unifocal circumscribed low-grade gliomas with a diameter of less than 4 cm in any location. The efficacy of this treatment lies in the same range as the best results after surgery and radiotherapy.

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Long-term outcome of stereotactic brachytherapy with temporary Iodine-125 seeds in patients with WHO grade II gliomas

Radiation Oncology ◽

10.1186/s13014-020-01719-9 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Juliana Watson ◽

Alexander Romagna ◽

Hendrik Ballhausen ◽

Maximilian Niyazi ◽

Stefanie Lietke ◽

...

Keyword(s):

Prognostic Factors ◽

Low Grade ◽

Toxicity Profile ◽

Who Grade ◽

Low Grade Gliomas ◽

Stereotactic Brachytherapy ◽

Grade Ii ◽

Iodine 125

Abstract Background This long-term retrospective analysis aimed to investigate the outcome and toxicity profile of stereotactic brachytherapy (SBT) in selected low-grade gliomas WHO grade II (LGGII) in a large patient series. Methods This analysis comprised 106 consecutive patients who received SBT with temporary Iodine-125 seeds for histologically verified LGGII at the University of Munich between March 1997 and July 2011. Investigation included clinical characteristics, technical aspects of SBT, the application of other treatments, outcome analyses including malignization rates, and prognostic factors with special focus on molecular biomarkers. Results For the entire study population, the 5- and 10-years overall survival (OS) rates were 79% and 62%, respectively, with a median follow-up of 115.9 months. No prognostic factors could be identified. Interstitial radiotherapy was applied in 51 cases as first-line treatment with a median number of two seeds (range 1–5), and a median total implanted activity of 21.8 mCi (range 4.2–43.4). The reference dose average was 54.0 Gy. Five- and ten-years OS and progression-free survival rates after SBT were 72% and 43%, and 40% and 23%, respectively, with a median follow-up of 86.7 months. The procedure-related mortality rate was zero, although an overall complication rate of 16% was registered. Patients with complications had a significantly larger tumor volume (p = 0.029). Conclusion SBT is a minimally invasive treatment modality with a favorable outcome and toxicity profile. It is both an alternative primary treatment method as well as an adjunct to open tumor resection in selected low-grade gliomas.

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PO-0995: Estimation of radiobiology parameters of infiltrative low-grade gliomas WHO Grade II

Radiotherapy and Oncology ◽

10.1016/s0167-8140(17)31431-7 ◽

2017 ◽

Vol 123 ◽

pp. S549 ◽

Cited By ~ 1

Author(s):

S. Milyukov ◽

Y. Lysak ◽

G. Panshin ◽

N. Kharchenko ◽

Z. Tsallagova ◽

...

Keyword(s):

Low Grade ◽

Who Grade ◽

Low Grade Gliomas ◽

Grade Ii

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BIOM-12. CIRCULATING TUMOR DNA IN ADULTS WITH GLIOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS OF BIOMARKER SENSITIVITY

Neuro-Oncology ◽

10.1093/neuonc/noaa215.012 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii3-ii4

Author(s):

James McMahon ◽

Matthew Studer ◽

Bryan Ulrich ◽

Gustavo Pradilla

Keyword(s):

Systematic Review ◽

Meta Analysis ◽

Circulating Tumor Dna ◽

Low Grade ◽

High Grade ◽

Who Grade ◽

Targeted Next Generation Sequencing ◽

Non Invasive ◽

Performance Statistics ◽

Tumor Dna

Abstract BACKGROUND Circulating tumor DNA (ctDNA) has emerged as a promising non-invasive biomarker to capture tumor genetics in patients with primary brain tumors. Research into its clinical utility, however, has not been standardized, as performance statistics of ctDNA remain undefined and optimal ctDNA assay and biospecimen sources for its evaluation have not been conclusively identified. We sought to determine a pooled sensitivity of the detection ctDNA in both CSF in plasma when compared to detecting the same mutant DNA in tumor tissue of gliomas. We then sought to compare ctDNA sensitivity between these two reservoirs, as well as between individual WHO grades of glioma. METHODS Following PRISMA guidelines, systematic review and meta-analysis was performed using published studies that assessed circulating tumor DNA in either plasma or CSF among adult patients with histopathology-confirmed glioma. Weighting of individual studies was conducted to reach an overall pooled sensitivity of ctDNA detection in both CSF and plasma. Chi-squared tests of independence were performed to compare overall sensitivity of ctDNA in CSF versus plasma, as well as to estimate the sensitivity of ctDNA for each WHO grade of glioma. RESULTS The overall reported sensitivity of ctDNA in CSF was found to be 77.4%, significantly higher than the 38.8% sensitivity in plasma (p< 0.0001). Sensitivity was significantly higher for high grade (82.8%) than low grade (60.5%) tumors in CSF (p=0.0023), and sensitivity was found to sequentially increase with increasing WHO grade. Qualitative analysis revealed evidence of greater sensitivity among single-allele PCR or small targeted next generation sequencing (NGS) panels, and increased sensitivity among larger tumors and those in proximity to cisternal or ventricular CSF. CONCLUSION Circulating tumor DNA is potentially a highly sensitive non-invasive biomarker among adults with gliomas. To maximize its sensitivity, CSF should be studied with targeted genetic analysis platforms, particularly in suspected high-grade gliomas.

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364 Tumor Compression Effect on White Matter Pathways Revealed by Local Connectome Fingerprint

Neurosurgery ◽

10.1093/neuros/nyx417.364 ◽

2017 ◽

Vol 64 (CN_suppl_1) ◽

pp. 284-285

Author(s):

Pinar Celtikci ◽

David Tiago Fernandes Cabral ◽

Yeh Fang-Cheng ◽

Sandip S Panesar ◽

Juan Carlos Fernandez-Miranda

Keyword(s):

White Matter ◽

Density Measurement ◽

High Angular Resolution ◽

Imaging Method ◽

Low Grade ◽

Who Grade ◽

Low Grade Gliomas ◽

Compression Effect ◽

Human Connectome Project ◽

Grade Ii

Abstract INTRODUCTION Low-grade gliomas (LGGs) are slow growing tumors that often cause infiltration and/or compression of the white matter pathways. Regular imaging modalities are no capable of revealing such a pathologic condition. Furthermore, up-to-date there is no reliable noninvasive imaging method to address this issue. Here we report that the local connectome fingerprint, an along track density measurement derived from diffusion MRI (dMRI), is capable of revealing the tumor compression effect on the surrounding white matter pathways. METHODS We acquired high angular resolution dMRI data on 16 patients diagnosed of LGG (WHO grade II). Peritumoral fiber tracts underwent qualitative and quantitative evaluation. Contralateral hemisphere counterparts were used for comparison. The local connectome fingerprint of peritumoral tract segment and their ratio to healthy side were visualized and calculated in comparison with 842 normal subjects from the Human Connectome Project. RESULTS >Our results showed significant increase in the ratios to the normal side among displaced tracts and decreases among the infiltrated tracts when compared to their healthy counterpart. Qualitative analysis of 65 peritumoral tracts revealed 9 (13.8%) unaffected, 24 (36.9%) displaced, 13 (20%) infiltrated and 19 (29.2%) tracts with a combination of displacement and infiltration. There were no disrupted tracts. The along tracks local connectome fingerprint further localizes the track segments with compression effect caused by the tumor mass. This feature cannot be observed in conventional tensor and diffusivity analysis. CONCLUSION The unique capability of local connectome fingerprint in revealing the compression and infiltration effect can provide potential diagnostic and prognostic applications in clinical intervention of patients with WHO grade-II low-grade gliomas.

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