The Clinical Utility of a Tiered Approach to Pediatric Glioma Molecular Characterization for Resource-Limited Settings.

PURPOSE: Molecular characterization is key to optimally diagnose and manage cancer. The complexity and cost of routine genomic analysis have unfortunately limited its use and denied many patients access to precision medicine. A possible solution is to rationalize use-creating a tiered approach to testing which uses inexpensive techniques for most patients and limits expensive testing to patients with the highest needs. Here, we tested the utility of this approach to molecularly characterize pediatric glioma in a cost- and time-sensitive manner. METHODS: We used a tiered testing pipeline of immunohistochemistry (IHC), customized fusion panels or fluorescence in situ hybridization (FISH), and targeted RNA sequencing in pediatric gliomas. Two distinct diagnostic algorithms were used for low- and high-grade gliomas (LGGs and HGGs). The percentage of driver alterations identified, associated testing costs, and turnaround time (TAT) are reported. RESULTS: The tiered approach successfully characterized 96% (95 of 99) of gliomas. For 82 LGGs, IHC, targeted fusion panel or FISH, and targeted RNA sequencing solved 35% (29 of 82), 29% (24 of 82), and 30% (25 of 82) of cases, respectively. A total of 64% (53 of 82) of samples were characterized without targeted RNA sequencing. Of 17 HGG samples, 13 were characterized by IHC and four were characterized by targeted RNA sequencing. The average cost per sample was more affordable when using the tiered approach as compared with up-front targeted RNA sequencing in LGG ($405 US dollars [USD] v $745 USD) and HGGs ($282 USD v $745 USD). The average TAT per sample was also shorter using the tiered approach (10 days for LGG, 5 days for HGG v 14 days for targeted RNA sequencing). CONCLUSION: Our tiered approach molecularly characterized 96% of samples in a cost- and time-sensitive manner. Such an approach may be feasible in neuro-oncology centers worldwide, particularly in resource-limited settings.

Comparison of Volumetric and 2D Measurements and Longitudinal Trajectories in the Response Assessment of BRAF V600E-Mutant Pediatric Gliomas in the Pacific Pediatric Neuro-Oncology Consortium Clinical Trial.

BACKGROUND AND PURPOSE: Response on imaging is widely used to evaluate treatment efficacy in clinical trials of pediatric gliomas. While conventional criteria rely on 2D measurements, volumetric analysis may provide a more comprehensive response assessment. There is sparse research on the role of volumetrics in pediatric gliomas. Our purpose was to compare 2D and volumetric analysis with the assessment of neuroradiologists using the Brain Tumor Reporting and Data System (BT-RADS) in BRAF V600E-mutant pediatric gliomas. MATERIALS AND METHODS: Manual volumetric segmentations of whole and solid tumors were compared with 2D measurements in 31 participants (292 follow-up studies) in the Pacific Pediatric Neuro-Oncology Consortium 002 trial (NCT01748149). Two neuroradiologists evaluated responses using BT-RADS. Receiver operating characteristic analysis compared classification performance of 2D and volumetrics for partial response. Agreement between volumetric and 2D mathematically modeled longitudinal trajectories for 25 participants was determined using the model-estimated time to best response. RESULTS: Of 31 participants, 20 had partial responses according to BT-RADS criteria. Receiver operating characteristic curves for the classification of partial responders at the time of first detection (median = 2 months) yielded an area under the curve of 0.84 (95% CI, 0.69-0.99) for 2D area, 0.91 (95% CI, 0.80-1.00) for whole-volume, and 0.92 (95% CI, 0.82-1.00) for solid volume change. There was no significant difference in the area under the curve between 2D and solid (P = .34) or whole volume (P = .39). There was no significant correlation in model-estimated time to best response (ρ = 0.39, P >.05) between 2D and whole-volume trajectories. Eight of the 25 participants had a difference of ≥90 days in transition from partial response to stable disease between their 2D and whole-volume modeled trajectories. CONCLUSIONS: Although there was no overall difference between volumetrics and 2D in classifying partial response assessment using BT-RADS, further prospective studies will be critical to elucidate how the observed differences in tumor 2D and volumetric trajectories affect clinical decision-making and outcomes in some individuals.

[PET/CT with 11C-methionine in assessment of brain glioma metabolism]. / Pozitronnaya emissionnaya tomografiya v sochetanii s komp'yuternoi tomografiei i 11S-metioninom v otsenke metabolizma gliom golovnogo mozga.

OBJECTIVE: To study 11C-methionine (MET) metabolism in gliomas using CNS tumor biobank imaging data. MATERIAL AND METHODS: MRI and 11C-MET PET/CT were performed in 225 patients (49±14 years, M/F=84/101) according to standard protocols with analysis of 11C-MET accumulation index and volumetric parameters (V_FLAIR, V_PET and V_PET/FLAIR). These results were compared with molecular genetic testing and 2-year overall survival. RESULTS: We examined 225 patients with gliomas (97 glioblastomas, 70 astrocytomas, 58 oligodendrogliomas). Accumulation index and volume of 11C-MET in glioblastomas were significantly higher in the general group (AI=2.90, Se 69%, Sp 76%, AUC 0.76; V_PET=24.3 cm3, Se 67%, Sp 60%, AUC 0.65; V_PET/FLAIR 0.46, Se 60%, Sp 69%, AUC 0.67) and within the group of astrocytomas (AI=2.93, Se 68%, Sp 89%, AUC 0.84; V_PET=8.06 cm3, Se 91%, Sp 35%, AUC 0.66; V_PET/FLAIR 0.27, Se 77%, Sp 60%, AUC 0.71). The median 2-year overall survival in patients with glioblastomas was 13 months that was significantly lower compared to IDH «+¼ gliomas (p<0.0001). There was a relationship between high accumulation index of 11C-MET and shorter overall survival in patients with glioblastomas. Significantly higher AI >3.59 (Se 89%, Sp 67%, AUC 0.79) was additionally obtained in subgroup of patients with glioblastomas >50 years (n=34) for EGFR «+¼ tumors. CONCLUSION: We found variable 11C-MET metabolism in WHO 2021 gliomas and confirmed significant difference in metabolic activity and volume of 11C-MET accumulation in glioblastomas compared to IDH «+¼ gliomas. Moreover, we revealed the relationship between high accumulation index and shorter survival. Analysis of 11C-MET metabolism in patients over 50 years old revealed higher accumulation index in the EGFR «+¼ group. Further comparison of these imaging methods and assessment of other significant mutations are necessary to identify the anatomical and metabolic patterns of IDH «+¼ gliomas.

Comparison of diagnostic performance of radiologist- and AI-based assessments of T2-FLAIR mismatch sign and quantitative assessment using synthetic MRI in the differential diagnosis between astrocytoma, IDH-mutant and oligodendroglioma, IDH-mutant and 1p/19q-codeleted.

PURPOSE: This study aimed to compare assessments by radiologists, artificial intelligence (AI), and quantitative measurement using synthetic MRI (SyMRI) for differential diagnosis between astrocytoma, IDH-mutant and oligodendroglioma, and IDH-mutant and 1p/19q-codeleted and to identify the superior method. METHODS: Thirty-three cases (men, 14; women, 19) comprising 19 astrocytomas and 14 oligodendrogliomas were evaluated. Four radiologists independently evaluated the presence of the T2-FLAIR mismatch sign. A 3D convolutional neural network (CNN) model was trained using 50 patients outside the test group (28 astrocytomas and 22 oligodendrogliomas) and transferred to evaluate the T2-FLAIR mismatch lesions in the test group. If the CNN labeled more than 50% of the T2-prolonged lesion area, the result was considered positive. The T1/T2-relaxation times and proton density (PD) derived from SyMRI were measured in both gliomas. Each quantitative parameter (T1, T2, and PD) was compared between gliomas using the Mann-Whitney U-test. Receiver-operating characteristic analysis was used to evaluate the diagnostic performance. RESULTS: The mean sensitivity, specificity, and area under the curve (AUC) of radiologists vs. AI were 76.3% vs. 94.7%; 100% vs. 92.9%; and 0.880 vs. 0.938, respectively. The two types of diffuse gliomas could be differentiated using a cutoff value of 2290/128 ms for a combined 90th percentile of T1 and 10th percentile of T2 relaxation times with 94.4/100% sensitivity/specificity with an AUC of 0.981. CONCLUSION: Compared to the radiologists' assessment using the T2-FLAIR mismatch sign, the AI and the SyMRI assessments increased both sensitivity and objectivity, resulting in improved diagnostic performance in differentiating gliomas.

Reliability assessment of methylthioadenosine phosphorylase immunohistochemistry as a surrogate biomarker for CDKN2A homozygous deletion in adult-type IDH-mutant diffuse gliomas.

According to the 2021 World Health Organization classification of brain tumors, astrocytomas containing a CDKN2A/B homozygous deletion (HD) are designated as grade 4 even when no microvascular proliferation and/or necrosis is present. In this study, we aimed to investigate the relationship between CDKN2A HD and loss of methylthioadenosine phosphorylase (MTAP) expression in adult-type IDH-mutant gliomas and to assess the sensitivity and specificity of MTAP immunohistochemistry (IHC) along with interobserver agreement as a surrogate biomarker for CDKN2A HD. Eighty-eight astrocytomas and 71 oligodendrogliomas cases that were diagnosed between 2014 and 2021 at Hacettepe University were selected and tissue microarrays were conducted to perform CDKN2A fluorescence in situ hybridization and MTAP IHC. Twenty-five (15.7%) cases harbored CDKN2A HD. MTAP loss was detected in 28 (15.7%) cases by the first observer and 27 (17%) cases by the second observer. The sensitivity and specificity of MTAP were calculated as 88% and 95.52%-96.27% for 2 observers. A very good/perfect agreement was noted between the observers (Cohen kappa coefficient = 0.938). Intratumoral heterogeneity was observed in 4 cases. MTAP IHC was found to be a reliable surrogate biomarker as a possible alternative to CDKN2A HD identification with a high sensitivity and specificity along with high interobserver agreement.

Radiogenomic landscape: Assessment of specific phagocytosis regulators in lower-grade gliomas.

Genome-wide CRISPR-Cas9 knockout screens have emerged as a powerful method for identifying key genes driving tumor growth. The aim of this study was to explore the phagocytosis regulators (PRs) specifically associated with lower-grade glioma (LGG) using the CRISPR-Cas9 screening database. Identifying these core PRs could lead to novel therapeutic targets and pave the way for a non-invasive radiogenomics approach to assess LGG patients' prognosis and treatment response. We selected 24 PRs that were overexpressed and lethal in LGG for analysis. The identified PR subtypes (PRsClusters, geneClusters, and PRs-score models) effectively predicted clinical outcomes in LGG patients. Immune response markers, such as CTLA4, were found to be significantly associated with PR-score. Nine radiogenomics models using various machine learning classifiers were constructed to uncover survival risk. The area under the curve (AUC) values for these models in the test and training datasets were 0.686 and 0.868, respectively. The CRISPR-Cas9 screen identified novel prognostic radiogenomics biomarkers that correlated well with the expression status of specific PR-related genes in LGG patients. These biomarkers successfully stratified patient survival outcomes and treatment response using The Cancer Genome Atlas (TCGA) database. This study has important implications for the development of precise clinical treatment strategies and holds promise for more accurate therapeutic approaches for LGG patients in the future.

Low-coverage and cost-effective whole-genome sequencing assay for glioma risk stratification.

PURPOSE: To investigate chromosomal instability (CIN) as a biomarker for glioma risk stratifications, with cost-effective, low-coverage whole-genome sequencing assay (WGS). METHODS: Thirty-five formalin-fixed paraffin-embedded glioma samples were collected from Huashan Hospital. DNA was sent for WGS by Illumina X10 at low (median) genome coverage of 1.86x (range: 1.03-3.17×), followed by copy number analyses, using a customized bioinformatics workflow-Ultrasensitive Copy number Aberration Detector. RESULTS: Among the 35 glioma patients, 12 were grade IV, 10 grade III, 11 grade II, and 2 Grade I cases, with high chromosomal instability (CIN +) in 24 (68.6%) of the glioma patients. The other 11 (31.4%) had lower chromosomal instability (CIN-). CIN significantly correlates with overall survival (P = 0.00029). Patients with CIN + /7p11.2 + (12 grade IV and 3 grade III) had the worst survival ratio (hazard ratio:16.2, 95% CI:6.3-41.6) with a median overall survival of 24 months. Ten (66.7%) patients died during the first two follow-up years. In the CIN + patients without 7p11.2 + (6 grade III, 3 grade II), 3 (33.3%) patients died during follow-up, and the estimated overall survival was around 65 months. No deaths were reported in the 11 CIN- patients (2 grade I, 8 grade II, 1 grade III) during the 80-month follow-up period. In this study, chromosomal instability served as a prognosis factor for gliomas independent of tumor grades. CONCLUSION: It is feasible to use cost-effective, low-coverage WGS for risk stratification of glioma. Elevated chromosomal instability is associated with poor prognosis.

[Analysis of the difference in MGMT promoter status in gliomas and its significance in prognosis assessment].

The data of 1 268 newly diagnosed gliomas from the Fourth Ward of Neurosurgery Department of Beijing Tiantan Hospital between April 2013 and March 2022 were retrospectively analyzed. Based on postoperative pathology, the gliomas were divided into groups: oligodendrogliomas (n=308), astrocytomas (n=337) and glioblastomas (n=623). According to the O6-methylguanine-DNA methyl transferase (MGMT) promoter status defined by the 12% of best cut-off value in previous research results, patients were divided into methylation group (n=763) and non-methylation group (n=505). Methylation level [M (Q1, Q3)] in patients with glioblastoma, astrocytoma and oligodendroglioma was 6% (2%, 24%), 17% (10%, 28%) and 29% (19%, 40%), respectively (P<0.001). Compared with non-methylation patients, the progression-free survival (PFS) and overall survival (OS) of glioblastomas patients with methylation of MGMT promoter demonstrated more favorable prognosis [M (Q1, Q3)]) of PFS: 14.0 (6.0, 36.0) months vs 8.0 (4.0, 15.0) months, P<0.001; M (Q1, Q3) of OS: 29.0 (17.0, 60.5) months vs 16.0 (11.0, 26.5) months, P<0.001]. In astrocytomas patients, the PFS was much longer for those with methylation [the median PFS of patients with methylation was not observed at the end of follow-up, but those without methylation showed a median PFS of 46.0 (29.0, 52.0) months] (P=0.001). However, no statistically significant difference was observed in OS [the median OS of patients with methylation was not observed at the end of follow-up, but those without methylation had a median OS of 62.0 (46.0, 98.0) months] (P=0.085). In oligodendrogliomas patients, no statistically significant differences of PFS and OS were observed between patients with methylation and those without methylation. MGMT promoter status was a related factor affecting PFS and OS in glioblastomas (PFS: HR=0.534,95%CI: 0.426-0.668, P<0.001; OS: HR=0.451, 95%CI: 0.353-0.576, P<0.001). Moreover, MGMT promoter status was also a related factor affecting PFS in astrocytomas (HR=0.462, 95%CI: 0.221-0.966, P=0.040), but not for OS (HR=0.664, 95%CI: 0.259-1.690, P=0.389). The methylation level of MGMT promoter differed substantially in different types of gliomas, and the status of MGMT promoter profoundly affected the prognosis of glioblastomas.

Deep Learning for Noninvasive Assessment of H3 K27M Mutation Status in Diffuse Midline Gliomas Using MR Imaging.

BACKGROUND: Determination of H3 K27M mutation in diffuse midline glioma (DMG) is key for prognostic assessment and stratifying patient subgroups for clinical trials. MRI can noninvasively depict morphological and metabolic characteristics of H3 K27M mutant DMG. PURPOSE: This study aimed to develop a deep learning (DL) approach to noninvasively predict H3 K27M mutation in DMG using T2-weighted images. STUDY TYPE: Retrospective and prospective. POPULATION: For diffuse midline brain gliomas, 341 patients from Center-1 (27 ± 19 years, 184 males), 42 patients from Center-2 (33 ± 19 years, 27 males) and 35 patients (37 ± 18 years, 24 males). For diffuse spinal cord gliomas, 133 patients from Center-1 (30 ± 15 years, 80 males). FIELD STRENGTH/SEQUENCE: 5T and 3T, T2-weighted turbo spin echo imaging. ASSESSMENT: Conventional radiological features were independently reviewed by two neuroradiologists. H3 K27M status was determined by histopathological examination. The Dice coefficient was used to evaluate segmentation performance. Classification performance was evaluated using accuracy, sensitivity, specificity, and area under the curve. STATISTICAL TESTS: Pearson's Chi-squared test, Fisher's exact test, two-sample Student's t-test and Mann-Whitney U test. A two-sided P value <0.05 was considered statistically significant. RESULTS: In the testing cohort, Dice coefficients of tumor segmentation using DL were 0.87 for diffuse midline brain and 0.81 for spinal cord gliomas. In the internal prospective testing dataset, the predictive accuracies, sensitivities, and specificities of H3 K27M mutation status were 92.1%, 98.2%, 82.9% in diffuse midline brain gliomas and 85.4%, 88.9%, 82.6% in spinal cord gliomas. Furthermore, this study showed that the performance generalizes to external institutions, with predictive accuracies of 85.7%-90.5%, sensitivities of 90.9%-96.0%, and specificities of 82.4%-83.3%. DATA CONCLUSION: In this study, an automatic DL framework was developed and validated for accurately predicting H3 K27M mutation using T2-weighted images, which could contribute to the noninvasive determination of H3 K27M status for clinical decision-making. EVIDENCE LEVEL: 2 Technical Efficacy: Stage 2.

Assessment of therapeutic outcome and role of reirradiation in patients with radiation-induced glioma.

BACKGROUND: We sought to clarify the optimal follow-up, therapeutic strategy, especially the role of reirradiation, and the diagnostic impact of isocitrate dehydrogenase (IDH) 1 and 2 mutation status in patients with radiation-induced glioma (RIG). METHODS: We retrospectively reviewed the clinical characteristics and treatment outcomes of 11 patients with high-grade glioma who satisfied Cahan's criteria for RIG in our database during 2001-2021. IDH 1/2 mutations were analyzed by Sanger sequencing and/or pyrosequencing. RESULTS: The RIGs included glioblastoma with IDH 1/2 wild-type (n = 7), glioblastoma not otherwise specified (n = 2), anaplastic astrocytoma with IDH1/2 wild-type (n = 1), and anaplastic astrocytoma not otherwise specified (n = 1). The median period from primary disease and RIG diagnosis was 17 years (range: 9-30 years). All patients underwent tumor removal or biopsy, 5 patients postoperatively received reirradiation combined with chemotherapy, and 6 patients were treated with chemotherapy alone. The median progression-free and survival times were 11.3 and 28.3 months. The median progression-free survival time of patients treated with reirradiation and chemotherapy (n = 5) tended to be longer than that of patients that received chemotherapy alone (n = 6) (17.0 vs 8.1 months). However, the median survival time was similar (29.6 vs 27.4 months). Local recurrence was observed in 5 patients treated with chemotherapy alone, whereas in 2 patients among 4 patients treated with reirradiation and chemotherapy. None of the patients developed radiation necrosis. In one case, the primary tumor was diffuse astrocytoma with IDH2 mutant, and the secondary tumor was glioblastoma with IDH 1/2 wild-type. Based on the difference of IDH2 mutation status, the secondary tumor with IDH 1/2 wild-type was diagnosed as a de novo tumor that was related to the previous radiation therapy. CONCLUSIONS: RIG can occur beyond 20 years after successfully treating the primary disease using radiotherapy; thus, cancer survivors should be informed of the long-term risk of developing RIG and the need for timely neuroimaging evaluation. Reirradiation combined with chemotherapy appears to be feasible and has favorable outcomes. Determining the IDH1/2 mutational status is useful to establish RIG diagnosis when the primary tumor is glioma.

Diagnostic test accuracy and cost-effectiveness of tests for codeletion of chromosomal arms 1p and 19q in people with glioma.

BACKGROUND: Complete deletion of both the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q), known as 1p/19q codeletion, is a mutation that can occur in gliomas. It occurs in a type of glioma known as oligodendroglioma and its higher grade counterpart known as anaplastic oligodendroglioma. Detection of 1p/19q codeletion in gliomas is important because, together with another mutation in an enzyme known as isocitrate dehydrogenase, it is needed to make the diagnosis of an oligodendroglioma. Presence of 1p/19q codeletion also informs patient prognosis and prediction of the best drug treatment. The main two tests in use are fluorescent in situ hybridisation (FISH) and polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) assays (also known as PCR-based short tandem repeat or microsatellite analysis). Many other tests are available. None of the tests is perfect, although PCR-based LOH is expected to have very high sensitivity. OBJECTIVES: To estimate the sensitivity and specificity and cost-effectiveness of different deoxyribonucleic acid (DNA)-based techniques for determining 1p/19q codeletion status in glioma. SEARCH METHODS: We searched MEDLINE, Embase and BIOSIS up to July 2019. There were no restrictions based on language or date of publication. We sought economic evaluation studies from the results of this search and using the National Health Service Economic Evaluation Database. SELECTION CRITERIA: We included cross-sectional studies in adults with glioma or any subtype of glioma, presenting raw data or cross-tabulations of two or more DNA-based tests for 1p/19q codeletion. We also sought economic evaluations of these tests. DATA COLLECTION AND ANALYSIS: We followed procedures outlined in the Cochrane Handbook for Diagnostic Test Accuracy Reviews. Two review authors independently screened titles/abstracts/full texts, performed data extraction, and undertook applicability and risk of bias assessments using QUADAS-2. Meta-analyses used the hierarchical summary ROC model to estimate and compare test accuracy. We used FISH and PCR-based LOH as alternate reference standards to examine how tests compared with those in common use, and conducted a latent class analysis comparing FISH and PCR-based LOH. We constructed an economic model to evaluate cost-effectiveness. MAIN RESULTS: We included 53 studies examining: PCR-based LOH, FISH, single nucleotide polymorphism (SNP) array, next-generation sequencing (NGS), comparative genomic hybridisation (CGH), array comparative genomic hybridisation (aCGH), multiplex-ligation-dependent probe amplification (MLPA), real-time PCR, chromogenic in situ hybridisation (CISH), mass spectrometry (MS), restriction fragment length polymorphism (RFLP) analysis, G-banding, methylation array and NanoString. Risk of bias was low for only one study; most gave us concerns about how patients were selected or about missing data. We had applicability concerns about many of the studies because only patients with specific subtypes of glioma were included. 1520 participants contributed to analyses using FISH as the reference, 1304 participants to analyses involving PCR-based LOH as the reference and 262 participants to analyses of comparisons between methods from studies not including FISH or PCR-based LOH. Most evidence was available for comparison of FISH with PCR-based LOH (15 studies, 915 participants): PCR-based LOH detected 94% of FISH-determined codeletions (95% credible interval (CrI) 83% to 98%) and FISH detected 91% of codeletions determined by PCR-based LOH (CrI 78% to 97%). Of tumours determined not to have a deletion by FISH, 94% (CrI 87% to 98%) had a deletion detected by PCR-based LOH, and of those determined not to have a deletion by PCR-based LOH, 96% (CrI 90% to 99%) had a deletion detected by FISH. The latent class analysis suggested that PCR-based LOH may be slightly more accurate than FISH. Most other techniques appeared to have high sensitivity (i.e. produced few false-negative results) for detection of 1p/19q codeletion when either FISH or PCR-based LOH was considered as the reference standard, although there was limited evidence. There was some indication of differences in specificity (false-positive rate) with some techniques. Both NGS and SNP array had high specificity when considered against FISH as the reference standard (NGS: 6 studies, 243 participants; SNP: 6 studies, 111 participants), although we rated certainty in the evidence as low or very low. NGS and SNP array also had high specificity when PCR-based LOH was considered the reference standard, although with much more uncertainty as these results were based on fewer studies (just one study with 49 participants for NGS and two studies with 33 participants for SNP array). G-banding had low sensitivity and specificity when PCR-based LOH was the reference standard. Although MS had very high sensitivity and specificity when both FISH and PCR-based LOH were considered the reference standard, these results were based on only one study with a small number of participants. Real-time PCR also showed high specificity with FISH as a reference standard, although there were only two studies including 40 participants. We found no relevant economic evaluations. Our economic model using FISH as the reference standard suggested that the resource-optimising test depends on which measure of diagnostic accuracy is most important. With FISH as the reference standard, MLPA is likely to be cost-effective if society was willing to pay GBP 1000 or less for a true positive detected. However, as the value placed on a true positive increased, CISH was most cost-effective. Findings differed when the outcome measure changed to either true negative detected or correct diagnosis. When PCR-based LOH was used as the reference standard, MLPA was likely to be cost-effective for all measures of diagnostic accuracy at lower threshold values for willingness to pay. However, as the threshold values increased, none of the tests were clearly more likely to be considered cost-effective. AUTHORS' CONCLUSIONS: In our review, most techniques (except G-banding) appeared to have good sensitivity (few false negatives) for detection of 1p/19q codeletions in glioma against both FISH and PCR-based LOH as a reference standard. However, we judged the certainty of the evidence low or very low for all the tests. There are possible differences in specificity, with both NGS and SNP array having high specificity (fewer false positives) for 1p/19q codeletion when considered against FISH as the reference standard. The economic analysis should be interpreted with caution due to the small number of studies.

Clinical and economic impact of molecular testing for BRAF fusion in pediatric low-grade Glioma.

BACKGROUND: Treatment personalization via tumor molecular testing holds promise for improving outcomes for patients with pediatric low-grade glioma (PLGG). We evaluate the health economic impact of employing tumor molecular testing to guide treatment for patients diagnosed with PLGG, particularly the avoidance of radiation therapy (RT) for patients with BRAF-fusion. METHODS: We performed a model-based cost-utility analysis comparing two strategies: molecular testing to determine BRAF fusion status at diagnosis against no molecular testing. We developed a microsimulation to model the lifetime health and cost outcomes (in quality-adjusted life years (QALYs) and 2018 CAD, respectively) for a simulated cohort of 100,000 patients newly diagnosed with PLGG after their initial surgery. RESULTS: The life expectancy after diagnosis for individuals who did not receive molecular testing was 39.01 (95% Confidence Intervals (CI): 32.94;44.38) years and 40.08 (95% CI: 33.19;45.76) years for those who received testing. Our findings indicate that patients who received molecular testing at diagnosis experienced a 0.38 (95% CI: 0.08;0.77) gain in QALYs and $1384 (95% CI: $-3486; $1204) reduction in costs over their lifetime. Cost and QALY benefits were driven primarily by the avoidance of long-term adverse events (stroke, secondary neoplasms) associated with unnecessary use of radiation. CONCLUSIONS: We demonstrate the clinical benefit and cost-effectiveness of molecular testing in guiding the decision to provide RT in PLGG. While our results do not consider the impact of targeted therapies, this work is an example of the value of simulation modeling in assessing the long-term costs and benefits of precision oncology interventions for childhood cancer, which can aid decision-making about health system reimbursement.

Advanced Imaging and Computational Techniques for the Diagnostic and Prognostic Assessment of Malignant Gliomas.

ABSTRACT: Advanced imaging techniques provide a powerful tool to assess the intratumoral and intertumoral heterogeneity of gliomas. Advances in the molecular understanding of glioma subgroups may allow improved diagnostic assessment combining imaging and molecular tumor features, with enhanced prognostic utility and implications for patient treatment. In this article, a comprehensive overview of the physiologic basis for conventional and advanced imaging techniques is presented, and clinical applications before and after treatment are discussed. An introduction to the principles of radiomics and the advanced integration of imaging, clinical outcomes, and genomic data highlights the future potential for this field of research to better stratify and select patients for standard as well as investigational therapies.

Magnetic resonance spectroscopy - its added value in brain glioma multiparametric assessment.

OBJECTIVE: In this study, we analysed the results of magnetic resonance spectroscopy (MRS) in the patients with gliomas, including the error rate, MRS parameters variability, correlations with gene mutations and overall usefulness for clinical practice. MATERIAL AND METHODS: Eighty patients with glial tumours were examined by multiparametric MRI completed with single voxel MRS, as one group, then as two separate groups according to progression of the disease after the initial surgery. The error rate between the groups, MRS parameters variability, hazard ratios and correlations between metabolites, genetic markers and tumour grade were all analysed. RESULTS: Variability in Cho/Cr(h) was significantly higher in the group with a disease progression (p = 0.044). In the patients with a stable disease, strong significant negative correlations between Cho/Cr and Cho/NAA with p53 mutation (-0.945 and -0.812 respectively, p < 0.05) and between Cho/Cr and IDH1, 2 mutation (-0.796, p < 0.05) were found. In the patients with tumour progression, a significant positive correlation of NAA/Cr with 1p19q codeletion (0.486, p < 0.05) and of Cho/Cr and Cho/NAA values with p53 mutation (0.477 and 0.416, p < 0.05) were identified. Tumour grade positively correlated with Cho/Cr values (0.304, p = 0.02) in the whole patient group. CONCLUSION: MRS brings an added value to multiparametric MRI evaluation of brain tumours in the patient follow-up after an initial surgery, especially in ambiguous findings (Tab. 5, Fig. 2, Ref. 29).

Next-Generation Sequencing Panel for 1p/19q Codeletion and IDH1-IDH2 Mutational Analysis Uncovers Mistaken Overdiagnoses of 1p/19q Codeletion by FISH.

The 1p/19q codeletion is the result of a translocation between chromosome 1 (Chr1p) and chromosome 19 (Chr19q) with the loss of derivative (1;19)(p10;q10) chromosome. The 1p/19q codeletion has predictive and prognostic significance, and it is essential for the classification of gliomas. In routine practice, the fluorescence in situ hybridization (FISH) diagnosis of 1p/19q codeletion is sometimes unexpected. This study aimed to develop a next-generation sequencing panel for the concurrent definition of the 1p/19q codeletion and IDH1/IDH2 mutation status to resolve these equivocal cases. A total of 65 glioma samples were investigated using a 1p/19q-single-nucleotide polymorphism (SNP)-IDH panel. The panel consists of 192 amplicons, including SNPs mapping to Chr1 and Chr19 and amplicons for IDH1/IDH2 analysis. The 1p/19q SNP-IDH panel consistently identified IDH1/IDH2 mutations. In 49 of 60 cases (81.7%), it provided the same 1p/19q results obtained by FISH. In the remaining 11 cases, the 1p/19q SNP-IDH panel uncovered partial chromosome imbalances as a result of interstitial amplification or deletion of the regions where the FISH probes map, leading to a mistaken overdiagnosis of 1p/19q codeletion by FISH. The 1p/19q SNP-IDH next-generation sequencing panel allows reliable analysis of the 1p/19q codeletion and IDH1/IDH2 mutation at the same time. The panel not only allows resolution of difficult cases but also represents a cost-effective alternative to standard molecular diagnostics procedures.

Noninvasive Assessment of O(6)-Methylguanine-DNA Methyltransferase Promoter Methylation Status in World Health Organization Grade II-IV Glioma Using Histogram Analysis of Inflow-Based Vascular-Space-Occupancy Combined with Structural Magnetic Resonance Imaging.

BACKGROUND: O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation is an important prognostic factor for gliomas and is associated with tumor angiogenesis. Arteriolar cerebral blood volume (CBVa) obtained from inflow-based vascular-space-occupancy (iVASO) magnetic resonance imaging (MRI) is assumed to be an indicator of tumor microvasculature. Its preoperative predictive ability for MGMT promoter methylation remains unclear. PURPOSE: To investigate the role of iVASO-CBVa histogram features in determining MGMT promoter methylation status of grade II-IV gliomas. STUDY TYPE: Retrospective SUBJECTS: Forty-six patients consisting of 20 MGMT methylated and 26 unmethylated gliomas. FIELD STRENGTH/SEQUENCE: 3.0 T magnetic resonance images containing iVASO MRI, T1 -weighted image (T1 WI), T2 -weighted image, T2 -weighted fluid attenuated inversion recovery image images, and enhanced T1 WI. ASSESSMENT: Sixteen structural imaging features were visually evaluated on structural MRI and 14 CBVa histogram features were extracted from iVASO-CBVa maps. STATISTICAL TESTS: Imaging features were screened and ranked using Fisher's exact test, Mann-Whitney U-test, and randomforest algorithm. Features with higher importance were selected to develop logistic regression models to determine MGMT methylation status. Receiver operating characteristics (ROC) curve with the area under the curve (AUC) and leave-one-out cross-validation (LOOCV) were used to assess effectiveness and stability. RESULTS: The top two CBVa histogram features were root mean squared (RMS) and variance. The top two structural imaging features were contrast-enhancing component of the tumor (CET) location and tumor location. Both the CBVa model of RMS and variance (ROC, AUC = 0.867; LOOCV, AUC = 0.819) and the model of structural features (ROC, AUC = 0.882; LOOCV, AUC = 0.802) accurately identified MGMT methylation. The fusion model of CBVa RMS and CET location improved diagnostic performance (ROC, AUC = 0.931; LOOCV, AUC =0.906). DATA CONCLUSION: iVASO-CBVa has potential in evaluating MGMT methylation status in grade II-IV gliomas. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 2.