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European Radiology Jul 2021To evaluate the diagnostic performance of the T2-FLAIR mismatch sign for prediction of isocitrate dehydrogenase (IDH)-mutant, 1p/19q-noncodeleted lower-grade gliomas... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
To evaluate the diagnostic performance of the T2-FLAIR mismatch sign for prediction of isocitrate dehydrogenase (IDH)-mutant, 1p/19q-noncodeleted lower-grade gliomas (LGGs) and review studies with false positive results.
METHODS
The MEDLINE and EMBASE databases were searched up to March 13, 2020, to identify articles reporting the diagnostic performance of the T2-FLAIR mismatch sign for prediction of IDH-mutant, 1p/19q-noncodeleted LGGs (IDHmut-Noncodel) using the search terms (T2 FLAIR mismatch). Pooled sensitivity, specificity, and correlation coefficient for interobserver agreement were calculated.
RESULTS
Twelve studies including a total of 1053 patients were included. The median age was 43 (median; range, 14-56). The pooled sensitivity and specificity were 42% (95% CI, 28-58%) and 100% (95% CI, 88-100%), respectively. According to the HSROC curve, the area under the curve was 0.77 (95% CI, 0.73-0.80). Considerable heterogeneity was possible among the studies in terms of both sensitivity and specificity. A threshold effect was suggested and was considered to explain most of the heterogeneity. Four studies reported false positive results for the T2-FLAIR mismatch sign, including dysembryoplastic neuroepithelial tumor, pediatric-type gliomas, and non-neoplastic lesions. The 2 original articles with false positive results showed the highest sensitivities among the 10 studies included in the quantitative analysis, supporting the probability of the threshold effect. The pooled correlation coefficient was 0.87 (95% CI, 0.73-0.94).
CONCLUSIONS
The T2-FLAIR mismatch sign had a high specificity and interobserver agreement for the prediction of IDHmut-Noncodel. However, the sign demonstrated low sensitivity, and a few studies with false positive cases were also reported.
KEY POINTS
• The pooled sensitivity and specificity of the T2-FLAIR mismatch sign for prediction of IDH-mutant, 1p/19q-noncodeleted lower-grade gliomas were 42% and 100%, respectively. • Four studies reported false positive results. • The pooled correlation coefficient was 0.87, suggesting almost perfect interobserver agreement.
Topics: Adult; Brain Neoplasms; Child; Glioma; Humans; Isocitrate Dehydrogenase; Magnetic Resonance Imaging; Mutation; Retrospective Studies
PubMed: 33409784
DOI: 10.1007/s00330-020-07467-4 -
Neuro-oncology Advances 2020Isocitrate dehydrogenase (IDH) mutation and 1p/19q-codeletion are oncogenetic alterations with a positive prognostic value for diffuse gliomas, especially grade II and... (Review)
Review
BACKGROUND
Isocitrate dehydrogenase (IDH) mutation and 1p/19q-codeletion are oncogenetic alterations with a positive prognostic value for diffuse gliomas, especially grade II and III. Some studies have suggested differences in biological behavior as reflected by radiological characteristics. In this paper, the literature regarding radiological characteristics in grade II and III glioma subtypes was systematically evaluated and a meta-analysis was performed.
METHODS
Studies that addressed the relationship between conventional radiological characteristics and IDH mutations and/or 1p/19q-codeletions in newly diagnosed, grade II and III gliomas of adult patients were included. The "3-group analysis" compared radiological characteristics between the WHO 2016 glioma subtypes (IDH-mutant astrocytoma, IDH-wildtype astrocytoma, and oligodendroglioma), and the "2-group analysis" compared radiological characteristics between 1p/19q-codeleted gliomas and 1p/19q-intact gliomas.
RESULTS
Fourteen studies (3-group analysis: 670 cases, 2-group analysis: 1042 cases) were included. IDH-mutated astrocytomas showed more often sharp borders and less frequently contrast enhancement compared to IDH-wildtype astrocytomas. 1p/19q-codeleted gliomas had less frequently sharp borders, but showed a heterogeneous aspect, calcification, cysts, and edema more frequently. For the 1p/19q-codeleted gliomas, a sensitivity of 96% was found for heterogeneity and a specificity of 88.1% for calcification.
CONCLUSIONS
Significant differences in conventional radiological characteristics exist between the WHO 2016 glioma subtypes, which may reflect differences in biological behavior. However, the diagnostic value of the independent radiological characteristics is insufficient to reliably predict the molecular genetic subtype.
PubMed: 32642698
DOI: 10.1093/noajnl/vdaa044 -
The Cochrane Database of Systematic... May 2020This is an updated version of the original Cochrane Review published in Issue 8, 2016. High grade glioma (HGG) is a rapidly growing brain tumour in the supporting cells... (Meta-Analysis)
Meta-Analysis
BACKGROUND
This is an updated version of the original Cochrane Review published in Issue 8, 2016. High grade glioma (HGG) is a rapidly growing brain tumour in the supporting cells of the nervous system, with several subtypes such as glioblastoma (grade IV astrocytoma), anaplastic (grade III) astrocytoma and anaplastic (grade III) oligodendroglioma. Studies have investigated the best strategy to give radiation to people with HGG. Conventional fractionated radiotherapy involves giving a daily radiation dose (called a fraction) of 180 cGy to 200 cGy. Hypofractionated radiotherapy uses higher daily doses, which reduces the overall number of fractions and treatment time. Hyperfractionated radiotherapy which uses a lower daily dose with a greater number of fractions and multiple fractions per day to deliver a total dose at least equivalent to external beam daily conventionally fractionated radiotherapy in the same time frame. The aim is to reduce the potential for late toxicity. Accelerated radiotherapy (dose escalation) refers to the delivery of multiple fractions per day using daily doses of radiation consistent with external beam daily conventionally fractionated radiotherapy doses. The aim is to reduce the overall treatment time; typically, two or three fractions per day may be delivered with a six to eight hour gap between fractions.
OBJECTIVES
To assess the effects of postoperative external beam radiation dose escalation in adults with HGG.
SEARCH METHODS
We searched CENTRAL, MEDLINE Ovid and Embase Ovid to August 2019 for relevant randomised phase III trials.
SELECTION CRITERIA
We included adults with a pathological diagnosis of HGG randomised to the following external beam radiation regimens: daily conventionally fractionated radiotherapy versus no radiotherapy; hypofractionated radiotherapy versus daily conventionally fractionated radiotherapy; hyperfractionated radiotherapy versus daily conventionally fractionated radiotherapy or accelerated radiotherapy versus daily conventionally fractionated radiotherapy.
DATA COLLECTION AND ANALYSIS
The primary outcomes were overall survival and adverse effects. The secondary outcomes were progression free survival and quality of life. We used the standard methodological procedures expected by Cochrane. We assessed the certainty of the evidence using the GRADE approach.
MAIN RESULTS
Since the last version of this review, we identified no new relevant trials for inclusion. We included 11 randomised controlled trials (RCTs) with 2062 participants and 1537 in the relevant arms for this review. There was an overall survival benefit for people with HGG receiving postoperative radiotherapy compared to the participants receiving postoperative supportive care. For the four pooled RCTs (397 participants), the overall hazard ratio (HR) for survival was 2.01 favouring postoperative radiotherapy (95% confidence interval (CI) 1.58 to 2.55; P < 0.00001; moderate-certainty evidence). Although these trials may not have completely reported adverse effects, they did not note any significant toxicity attributable to radiation. Progression free survival and quality of life could not be pooled due to lack of data. Overall survival was similar between hypofractionated and conventional radiotherapy in five trials (943 participants), where the HR was 0.95 (95% CI 0.78 to 1.17; P = 0.63; very low-certainty evidence. The trials reported that hypofractionated and conventional radiotherapy were well tolerated with mild acute adverse effects. These trials only reported one participant in the hypofractionated arm developing symptomatic radiation necrosis that required surgery. Progression free survival and quality of life could not be pooled due to the lack of data. Overall survival was similar between hypofractionated and conventional radiotherapy in the subset of two trials (293 participants) which included participants aged 60 years and older with glioblastoma. For this category, the HR was 1.16 (95% CI 0.92 to 1.46; P = 0.21; high-certainty evidence). There were two trials which compared hyperfractionated radiotherapy versus conventional radiation and one trial which compared accelerated radiotherapy versus conventional radiation. However, the results could not be pooled. The conventionally fractionated radiotherapy regimens were 4500 cGy to 6000 cGy given in 180 cGy to 200 cGy daily fractions, over five to six weeks. All trials generally included participants with World Health Organization (WHO) performance status from 0 to 2 and Karnofsky performance status of 50 and higher. The risk of selection bias was generally low among these RCTs. The number of participants lost to follow-up for the outcome of overall survival was low. Attrition, performance, detection and reporting bias for the outcome of overall survival was low. There was unclear attrition, performance, detection and reporting bias relating to the outcomes of adverse effects, progression free survival and quality of life.
AUTHORS' CONCLUSIONS
Postoperative conventional daily radiotherapy probably improves survival for adults with good performance status and HGG compared to no postoperative radiotherapy. Hypofractionated radiotherapy has similar efficacy for survival compared to conventional radiotherapy, particularly for individuals aged 60 years and older with glioblastoma. There are insufficient data regarding hyperfractionation versus conventionally fractionated radiation (without chemotherapy) and for accelerated radiation versus conventionally fractionated radiation (without chemotherapy). There are HGG subsets who have poor prognosis even with treatment (e.g. glioblastoma histology, older age and poor performance status). These HGG individuals with poor prognosis have generally been excluded from randomised trials based on poor performance status. No randomised trial has compared comfort measures or best supportive care with an active intervention using radiotherapy or chemotherapy in these people with poor prognosis. Since the last version of this review, we found no new relevant studies. The search identified three new trials, but all were excluded as none had a conventionally fractionated radiotherapy arm.
Topics: Adult; Age Factors; Aged; Brain Neoplasms; Cranial Irradiation; Disease-Free Survival; Dose Fractionation, Radiation; Glioma; Humans; Middle Aged; Quality of Life; Randomized Controlled Trials as Topic; Survival Analysis
PubMed: 32437039
DOI: 10.1002/14651858.CD011475.pub3 -
The Cochrane Database of Systematic... Jan 2020This is an update of the review originally published in 2011 and first updated in 2015. In most people with low-grade gliomas (LGG), the primary treatment regimen... (Meta-Analysis)
Meta-Analysis
BACKGROUND
This is an update of the review originally published in 2011 and first updated in 2015. In most people with low-grade gliomas (LGG), the primary treatment regimen remains a combination of surgery followed by postoperative radiotherapy. However, the optimal timing of radiotherapy is controversial. It is unclear whether to use radiotherapy in the early postoperative period, or whether radiotherapy should be delayed until tumour progression occurs.
OBJECTIVES
To assess the effects of early postoperative radiotherapy versus radiotherapy delayed until tumour progression for low-grade intracranial gliomas in people who had initial biopsy or surgical resection.
SEARCH METHODS
Original searches were run up to September 2014. An updated literature search from September 2014 through November 2019 was performed on the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 11), MEDLINE via Ovid (September 2014 to November week 2 2019), and Embase via Ovid (September 2014 to 2019 week 46) to identify trials for inclusion in this Cochrane review update.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that compared early versus delayed radiotherapy following biopsy or surgical resection for the treatment of people with newly diagnosed intracranial LGG (astrocytoma, oligodendroglioma, mixed oligoastrocytoma, astroblastoma, xanthoastrocytoma, or ganglioglioma). Radiotherapy may include conformal external beam radiotherapy (EBRT) with linear accelerator or cobalt-60 sources, intensity-modulated radiotherapy (IMRT), or stereotactic radiosurgery (SRS).
DATA COLLECTION AND ANALYSIS
Three review authors independently assessed the trials for inclusion and risk of bias, and extracted study data. We resolved any differences between review authors by discussion. Adverse effects were also extracted from the study report. We performed meta-analyses using a random-effects model with inverse variance weighting.
MAIN RESULTS
We included one large, multi-institutional, prospective RCT, involving 311 participants; the risk of bias in this study was unclear. This study found that early postoperative radiotherapy was associated with an increase in time to progression compared to observation (and delayed radiotherapy upon disease progression) for people with LGG but did not significantly improve overall survival (OS). The median progression-free survival (PFS) was 5.3 years in the early radiotherapy group and 3.4 years in the delayed radiotherapy group (hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.45 to 0.77; P < 0.0001; 311 participants; 1 trial; low-quality evidence). The median OS in the early radiotherapy group was 7.4 years, while the delayed radiotherapy group experienced a median overall survival of 7.2 years (HR 0.97, 95% CI 0.71 to 1.33; P = 0.872; 311 participants; 1 trial; low-quality evidence). The total dose of radiotherapy given was 54 Gy; five fractions of 1.8 Gy per week were given for six weeks. Adverse effects following radiotherapy consisted of skin reactions, otitis media, mild headache, nausea, and vomiting. Rescue therapy was provided to 65% of the participants randomised to delayed radiotherapy. People in both cohorts who were free from tumour progression showed no differences in cognitive deficit, focal deficit, performance status, and headache after one year. However, participants randomised to the early radiotherapy group experienced significantly fewer seizures than participants in the delayed postoperative radiotherapy group at one year (25% versus 41%, P = 0.0329, respectively).
AUTHORS' CONCLUSIONS
Given the high risk of bias in the included study, the results of this analysis must be interpreted with caution. Early radiation therapy was associated with the following adverse effects: skin reactions, otitis media, mild headache, nausea, and vomiting. People with LGG who underwent early radiotherapy showed an increase in time to progression compared with people who were observed and had radiotherapy at the time of progression. There was no significant difference in overall survival between people who had early versus delayed radiotherapy; however, this finding may be due to the effectiveness of rescue therapy with radiation in the control arm. People who underwent early radiation had better seizure control at one year than people who underwent delayed radiation. There were no cases of radiation-induced malignant transformation of LGG. However, it remained unclear whether there were differences in memory, executive function, cognitive function, or quality of life between the two groups since these measures were not evaluated.
Topics: Brain Neoplasms; Disease-Free Survival; Glioma; Humans; Postoperative Care; Progression-Free Survival; Radiosurgery; Radiotherapy; Randomized Controlled Trials as Topic; Time Factors; Watchful Waiting
PubMed: 31958162
DOI: 10.1002/14651858.CD009229.pub3 -
Neurosurgical Focus Dec 2019With the revised WHO 2016 classification of brain tumors, there has been increasing interest in imaging biomarkers to predict molecular status and improve the yield of...
The T2-FLAIR-mismatch sign as an imaging biomarker for IDH and 1p/19q status in diffuse low-grade gliomas: a systematic review with a Bayesian approach to evaluation of diagnostic test performance.
OBJECTIVE
With the revised WHO 2016 classification of brain tumors, there has been increasing interest in imaging biomarkers to predict molecular status and improve the yield of genetic testing for diffuse low-grade gliomas (LGGs). The T2-FLAIR-mismatch sign has been suggested to be a highly specific radiographic marker of isocitrate dehydrogenase (IDH) gene mutation and 1p/19q codeletion status in diffuse LGGs. The presence of T2-FLAIR mismatch indicates a T2-hyperintense lesion that is hypointense on FLAIR with the exception of a hyperintense rim.
METHODS
In accordance with PRISMA guidelines, we performed a systematic review of the Ovid Medline, Embase, Scopus, and Cochrane databases for reports of studies evaluating the diagnostic performance of T2-FLAIR mismatch in predicting the IDH and 1p/19q codeletion status in diffuse LGGs. Results were combined into a 2 × 2 format, and the following diagnostic performance parameters were calculated: sensitivity, specificity, positive predictive value, negative predictive value, and positive (LR+) and negative (LR-) likelihood ratios. In addition, we utilized Bayes theorem to calculate posttest probabilities as a function of known pretest probabilities from previous genome-wide association studies and the calculated LRs. Calculations were performed for 1) IDH mutation with 1p/19q codeletion (IDHmut-Codel), 2) IDH mutation without 1p/19q codeletion (IDHmut-Noncodel), 3) IDH mutation overall, and 4) 1p/19q codeletion overall. The QUADAS-2 (revised Quality Assessment of Diagnostic Accuracy Studies) tool was utilized for critical appraisal of included studies.
RESULTS
A total of 4 studies were included, with inclusion of 2 separate cohorts from a study reporting testing and validation (n = 746). From pooled analysis of all cohorts, the following values were obtained for each molecular profile-IDHmut-Codel: sensitivity 30%, specificity 73%, LR+ 1.1, LR- 1.0; IDHmut-Noncodel: sensitivity 33.7%, specificity 98.5%, LR+ 22.5, LR- 0.7; IDH: sensitivity 32%, specificity 100%, LR+ 32.1, LR- 0.7; 1p/19q codeletion: sensitivity 0%, specificity 54%, LR+ 0.01, LR- 1.9. Bayes theorem was used to calculate the following posttest probabilities after a positive and negative result, respectively-IDHmut-Codel: 32.2% and 29.4%; IDHmut-Noncodel: 95% and 40%; IDH: 99.2% and 73.5%; 1p/19q codeletion: 0.4% and 35.1%.
CONCLUSIONS
The T2-FLAIR-mismatch sign is an insensitive but highly specific marker of IDH mutation but not 1p/19q codeletion in diffuse LGGs, although there may be significant exceptions. These findings support the utility of T2-FLAIR mismatch as an imaging-based biomarker for positive selection of patients with IDH-mutant gliomas.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Brain Neoplasms; Chromosomes, Human, Pair 1; DNA Mutational Analysis; Female; Gene Deletion; Glioma; Humans; Isocitrate Dehydrogenase; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Proteins; Neuroimaging; Predictive Value of Tests; Sensitivity and Specificity; Young Adult
PubMed: 31786548
DOI: 10.3171/2019.9.FOCUS19660 -
World Neurosurgery Jan 2020With the 2016 update of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System incorporating molecular subtyping to histology, WHO...
Effect of Treatment Modalities on Progression-Free Survival and Overall Survival in Molecularly Subtyped World Health Organization Grade II Diffuse Gliomas: A Systematic Review.
BACKGROUND
With the 2016 update of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System incorporating molecular subtyping to histology, WHO grade II diffuse astrocytic and oligodendroglial tumors are subcategorized by distinct molecular markers. There are no reported systematic reviews quantifying differences in progression-free survival (PFS) and overall survival (OS) on the basis of molecular subtypes of WHO grade II diffuse gliomas, against the background of administered treatments.
METHODS
Using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and the Cochrane Handbook of Systemic Reviews of Interventions, we conducted a systematic review through MEDLINE, Embase, and CENTRAL (Cochrane Central Register of Controlled Trails).
RESULTS
For OS, the first quartile (25%), median (50%), third quartile (75%), and 95% confidence interval, respectively, were identified (in months): astrocytoma-wild-type WHO II (A-wt II): 22.8, 32.2, 40.7, and 21.6-61.2; astrocytoma-mutant WHO II (A-mt II): 69.85, 115.2, 128.4, and 55.4-164.0; oligodendroglioma WHO II (OD-II): 106.3, 163.7, 213.3, and 67.3-235.4 (P value = 0.0002). For PFS, the 25th, 50th, and 75th percentiles, and 95% confidence interval, respectively, are as follows (in months): A-wt II: 6.90, 17.45, 19.57, and 3.00-23.69; A-mt II: 37.20, 43.20, 55.63, and 35.7-60.0; OD-II: 47.42, 59.2, 88.28, and 46.3-91.2 (P value = 0.015).
CONCLUSIONS
This seems to be the first systematic review of OS and PFS in patients with WHO grade II low-grade gliomas (LGGs), against treatment modalities, in molecularly stratified subsets introduced by the WHO 2016 classification of central nervous system tumors. Overall, A-wt II was confirmed to have a significantly shorter OS than did A-mt II; no significant difference was found between OS of OD-II with A-wt II and A-mt II. In addition, all 3 molecular subtypes were found to have statistically significant differences between PFS, with OD-II having a statistically better PFS than A-mt II. These data can provide valuable prognostic insight to patients and clinicians. In addition, assessing survival differences enhances understanding of treatment recommendations against molecular markers and may facilitate future clinical trial design.
Topics: Brain Neoplasms; Glioma; Humans; Neoplasm Grading; Progression-Free Survival; Survival Rate
PubMed: 31473344
DOI: 10.1016/j.wneu.2019.08.111