Amide proton transfer weighted and diffusion weighted imaging based radiomics classification algorithm for predicting 1p/19q co-deletion status in low grade gliomas.

BACKGROUND: 1p/19q co-deletion in low-grade gliomas (LGG, World Health Organization grade II and III) is of great significance in clinical decision making. We aim to use radiomics analysis to predict 1p/19q co-deletion in LGG based on amide proton transfer weighted (APTw), diffusion weighted imaging (DWI), and conventional MRI. METHODS: This retrospective study included 90 patients histopathologically diagnosed with LGG. We performed a radiomics analysis by extracting 8454 MRI-based features form APTw, DWI and conventional MR images and applied a least absolute shrinkage and selection operator (LASSO) algorithm to select radiomics signature. A radiomics score (Rad-score) was generated using a linear combination of the values of the selected features weighted for each of the patients. Three neuroradiologists, including one experienced neuroradiologist and two resident physicians, independently evaluated the MR features of LGG and provided predictions on whether the tumor had 1p/19q co-deletion or 1p/19q intact status. A clinical model was then constructed based on the significant variables identified in this analysis. A combined model incorporating both the Rad-score and clinical factors was also constructed. The predictive performance was validated by receiver operating characteristic curve analysis, DeLong analysis and decision curve analysis. P < 0.05 was statistically significant. RESULTS: The radiomics model and the combined model both exhibited excellent performance on both the training and test sets, achieving areas under the curve (AUCs) of 0.948 and 0.966, as well as 0.909 and 0.896, respectively. These results surpassed the performance of the clinical model, which achieved AUCs of 0.760 and 0.766 on the training and test sets, respectively. After performing Delong analysis, the clinical model did not significantly differ in predictive performance from three neuroradiologists. In the training set, both the radiomic and combined models performed better than all neuroradiologists. In the test set, the models exhibited higher AUCs than the neuroradiologists, with the radiomics model significantly outperforming resident physicians B and C, but not differing significantly from experienced neuroradiologist. CONCLUSIONS: Our results suggest that our algorithm can noninvasively predict the 1p/19q co-deletion status of LGG. The predictive performance of radiomics model was comparable to that of experienced neuroradiologist, significantly outperforming the diagnostic accuracy of resident physicians, thereby offering the potential to facilitate non-invasive 1p/19q co-deletion prediction of LGG.

Artificial Intelligence Applications in Glioma With 1p/19q Co-Deletion: A Systematic Review.

As an important genomic marker for oligodendrogliomas, early determination of 1p/19q co-deletion status is critical for guiding therapy and predicting prognosis in patients with glioma. The purpose of this study is to systematically review the literature concerning the magnetic resonance imaging (MRI) with artificial intelligence (AI) methods for predicting 1p/19q co-deletion status in glioma. PubMed, Scopus, Embase, and IEEE Xplore were searched in accordance with the Preferred Reporting Items for systematic reviews and meta-analyses guidelines. Methodological quality of studies was assessed according to the Quality Assessment of Diagnostic Accuracy Studies-2. Finally, 28 studies were included in the quantitative analysis. Diagnostic test accuracy reached an area under the ROC curve of 0.71-0.98 were reported in 24 studies. The remaining four studies with no available AUC provided an accuracy of 0.75-0. 89. The included studies varied widely in terms of imaging sequences, input features, and modeling methods. The current review highlighted that integrating MRI with AI technology is a potential tool for determination 1p/19q status pre-operatively and noninvasively, which can possibly help clinical decision-making. However, the reliability and feasibility of this approach still need to be further validated and improved in a real clinical setting. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: 2.

Impact of IDH Mutations, the 1p/19q Co-Deletion and the G-CIMP Status on Alternative Splicing in Diffuse Gliomas.

By generating protein diversity, alternative splicing provides an important oncogenic pathway. Isocitrate dehydrogenase (IDH) 1 and 2 mutations and 1p/19q co-deletion have become crucial for the novel molecular classification of diffuse gliomas, which also incorporates DNA methylation profiling. In this study, we have carried out a bioinformatics analysis to examine the impact of the IDH mutation, as well as the 1p/19q co-deletion and the glioma CpG island methylator phenotype (G-CIMP) status on alternative splicing in a cohort of 662 diffuse gliomas from The Cancer Genome Atlas (TCGA). We identify the biological processes and molecular functions affected by alternative splicing in the various glioma subgroups and provide evidence supporting the important contribution of alternative splicing in modulating epigenetic regulation in diffuse gliomas. Targeting the genes and pathways affected by alternative splicing might provide novel therapeutic opportunities against gliomas.

Histogram-based analysis of cerebral blood flow using arterial spin labeling MRI in de novo brain gliomas: relationship to histopathologic grade and molecular markers.

PURPOSE: We developed multiple histogram-based CBF indices and evaluated their association with histopathologic grade in de novo brain tumor patients. Furthermore, the associations between these advanced CBF indices and molecular markers, including IDH1 mutation, ATRX loss, and 1p/19q co-deletion were also investigated. METHODS: Thirteen de novo brain tumor patients (age 21-68 years, 9 M/4F) who were enrolled in our prospective study were scanned on 3 T MRI using a pCASL perfusion sequence following IRB-approved written informed consent. All patients have since undergone surgical intervention with tissue sampling for histopathologic tumor grading and molecular marker assessment. Tumor region of interest (ROI) were manually delineated on FLAIR images including the full extent of the tumor and peritumoral edema. Fourteen rCBF indices were derived from the histogram of the voxels with the ROI. Multi-linear regression was then used to compare rCBF indices with histopathologic tumor grade and molecular markers. RESULTS: Averaged rCBF in top 10 and top 20 voxels (p < 0.004), but not the entire tumor ROI, was positively associated with WHO tumor grade. After accounting for tumor grade, the presence of 1p/19q co-deletion was associated with higher rCBF in top voxels, as well as with standard deviation of rCBF in the tumor ROI (p < 0.001). ATRX retention was related to higher rCBF, and this effect appears to be present in both higher-perfusion (p < 0.004) and low-perfusion (p < 0.05) voxels. IDH mutation was not significantly associated with any of the CBF indices investigated. CONCLUSION: ASL MRI may provide useful supplemental noninvasive imaging assessment of brain tumor grade and molecular marker status.

Is the anatomical distribution of low-grade gliomas linked to regions of gliogenesis?

INTRODUCTION: According to the stem cell theory, two neurogenic niches in the adult human brain may harbor cells that initiate the formation of gliomas: The larger subventricular zone (SVZ) and the subgranular zone (SGZ) in the hippocampus. We wanted to explore whether defining molecular markers in low-grade gliomas (LGG; WHO grade II) are related to distance to the neurogenic niches. METHODS: Patients treated at two Norwegian university hospitals with population-based referral were included. Eligible patients had histopathological verified supratentorial low-grade glioma. IDH mutational status and 1p19q co-deletion status was retrospectively assessed. 159 patients were included, and semi-automatic tumor segmentation was done from pre-treatment T2-weighted (T2W) or Fluid-Attenuated Inversion Recovery (FLAIR) images. 3D maps showing the anatomical distribution of the tumors were then created for each of the three molecular subtypes (IDH mutated/1p19q co-deleted, IDH mutated and IDH wild-type). Both distance from tumor center and tumor border to the neurogenic niches were recorded. RESULTS: In this population-based cohort of previously untreated low-grade gliomas, we found that low-grade gliomas are more often found closer to the SVZ than the SGZ, but IDH wild-type tumors are more often found near SGZ. CONCLUSION: Our study suggests that the stem cell origin of IDH wild-type and IDH mutated low-grade gliomas may be different.

Clinical impact of revisions to the WHO classification of diffuse gliomas and associated future problems.

The publication of the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 WHO CNS) represented a major change in the classification of brain tumors. It is essential to determine the IDH and 1p/19q statuses of diffuse gliomas to ensure that the final diagnosis is accurate. The integrated diagnostic method outlined in the 2016 WHO CNS has enabled more precise prediction of the prognoses of diffuse gliomas. However, there are further two points that need to be addressed when planning future clinical trials. The first is the problems with the WHO grading system for diffuse gliomas. The second is that examinations for IDH mutations and 1p/19q co-deletion are not sufficient on their own to accurately predict the prognosis of diffuse glioma patients. Risk of an IDH-mut diffuse glioma should be evaluated based on a combination of clinical factors (age and the resection rate), molecular factors (the presence/absence of CDKN2A deletion), and histological factors (morphology and the mitotic index). Glioblastoma (GBM) have also been classified according to their IDH status; however, the frequency of IDH gene mutations is only 5-10% in GBM. Other molecular markers such as MGMT methylation, pTERT mutations and EGFR amplification could be more important to predict clinical outcome. Therefore, the next revision of the classification of diffuse gliomas will propose a detailed classification based on additional markers. In the near future, treatments for diffuse gliomas will be chosen according to the molecular profile of each tumor.

1p/19q co-deleted fibrillary astrocytomas: Not everything that is co-deleted is an oligodendroglioma.

The presence of chromosome 1p/19q co-deletion is one of the hallmark required criteria for the diagnosis of oligodendroglioma, using the 2016 World Health Organization (WHO) Classification of Tumours of the Central Nervous System. Descriptions in the literature of astrocytomas, primarily glioblastomas, demonstrating partial losses on one or the other chromosome have been described. The significance of these small deletions is uncertain. Only rarely have cases of fibrillary astrocytoma been described as having co-deletion, which may potentially cause diagnostic confusion with oligodendroglioma. The goal of this study is to examine a large number of fibrillary astrocytomas to document how often 1p/19q co-deletions are present by Fluorescent In Situ Hybridization (FISH) testing (the testing method of choice in many institutions) and to evaluate what other markers may be helpful in avoiding misdiagnosis. This study is a retrospective evaluation of 359 fibrillary astrocytomas (55 grade II, 62 grade III and 242 grade IV) encountered between June 2016 and June 2019, we identified 11 tumors (3.1%) that had 1p/19q co-deletion by FISH testing. The clinical and pathologic features of these cases were reviewed. The 11 cases with co-deletion included 5 females who ranged in age from 37 to 86 years (median 63 years). Tumors arose in the temporal lobe in 5 patients, frontal lobe in 2, parietal lobe in 2, occipital lobe in 1, and cerebellum in 1. Final diagnoses included glioblastoma in 8 patients, anaplastic astrocytoma in 2, and diffuse astrocytoma in 1. Only 1 case (anaplastic astrocytoma) demonstrated evidence of IDH-1 immunoreactivity; none of the other 10 tumors showed evidence of an IDH1/2 mutation by PCR testing. Four tumors demonstrated p53 immunostaining of 30% or more. ATRX mutation as evidenced by loss of staining was observed in only 2 cases. Evidence of EGFR amplification by FISH testing was noted in 5 cases. Of particular note in the one case that demonstrated both 1p/19q co-deletion and an IDH-1 mutation, LOH testing was done and showed only partial losses on both chromosomes. Additionally, this tumor also demonstrated evidence of ATRX and p53 mutations by immunohistochemistry. In conclusion, co-deletions were noted in a minority of astrocytomas (3.1% of cases in the current study). Only 1 of 11 of these cases also demonstrated evidence of an IDH mutation, potentially raising differential diagnostic confusion with oligodendroglioma. Use of LOH 1p/19q testing, if available, or other markers such as ATRX, p53 and EGFR may be helpful in avoiding misclassification of such tumors as oligodendroglioma.

Observation after surgery for low grade glioma: long-term outcome in the light of the 2016 WHO classification.

PURPOSE: To provide detailed long-term data after initial observation for patients after histological confirmation of low grade (WHO II) gliomas according to molecular stratification. METHODS: A series of 110 patients with watchful waiting strategy after initial surgery for LGG and re-surgery at tumor progression were analyzed. Progression-free survival, time to malignant transformation, post-recurrence survival, and overall survival were estimated with the Kaplan-Meier method. Prognostic factors were identified by the Log Rank test and Cox multivariate proportional hazards model. RESULTS: The cohort comprised 18 IDH wild type (IDHwt) and 53 IDH mutated (IDHmut) astrocytomas, and 39 IDH mutated and 1p 19q co-deleted (IDHmut/codel) patients. The median follow-up was 126 (95% CI 109-143) months. Surgery was gross total resection in 58, subtotal resection in 28, and biopsy in 24 patients. Progression-free survival rates at 5, 10 and 15 years was 38% 18% and 1%. The corresponding malignant transformation rates were 17%, 39% and 71%. The initial extent of resection influenced progression-free survival, time to malignant transformation and overall survival. Molecular subtype IDHmut/codel was the strongest prognostic factor for overall survival and for time to malignant transformation. CONCLUSION: The strongest determinant of the patients' course after initial watchful waiting was the molecular tumor status. Extensive resection may increase time to progression and malignant transformation. Observation may be justified in selected patients.

Unusual radiological and histological presentation of a diffuse leptomeningeal glioneuronal tumor (DLGNT) in a 13-year-old girl.

Diffuse leptomeningeal glioneuronal tumors (DLGNTs) are newly recognized as an entity in the 2016 revision of the WHO Classification of tumors of the central nervous system. They typically present as diffuse leptomeningeal infiltrates along the neuraxis with focal and superficial involvement of the parenchyma. Here, we report a DLGNT with unusual radiological and histological features. A 13-year-old girl presented with scoliosis and back pain. Magnetic resonance imaging demonstrated a syrinx from C2 to T11 and an intramedullary mass from T6 to T9-10. No leptomeningeal involvement was recognized. Histological examination of the gross total resection specimen revealed a low-grade neuroepithelial neoplasm predominantly infiltrating the spinal cord and only focally involving the leptomeninges. Chromosome microarray identified co-deletion of the short arm of chromosome 1 and the long arm of chromosome 19 as well as fusion of the KIAA1549 and BRAF genes. Next-generation sequencing demonstrated wild-type alleles at the mutational hotspots of IDH1 (R132) and IDH2 (R140 and R172). In contrast to most reported DLGNTs, the tumor described in this manuscript was characterized by a predominant parenchymal component and only minor leptomeningeal involvement both radiographically and histologically. Our case, therefore, expands the spectrum of radiological and histopathological features of this new entity. It also highlights the critical role of molecular genetic testing in establishing the diagnosis of DLGNT in unusual cases.

ATRX immunohistochemistry can help refine 'not elsewhere classified' categorisation for grade II/III gliomas.

Purpose: The 2016 WHO tumour classification highlights the role of IDH1/2 gene mutation and 1p/19q co-deletion in classifying grade II/III gliomas. A recent cIMPACT-NOW update proposes the use of the term 'Not Elsewhere Classified' (NEC) for IDH-mutant, non co-deleted tumours. Here we show how the incorporation of ATRX immunohistochemistry can be used to better delineate the NEC group. Methods: Clinical data was collected for 112 patients (59% male) treated at our unit. Mutations in IDH1/2 genes were detected by pyrosequencing or immunohistochemistry, 1p/19q co-deletion was assessed with fluorescence in situ hybridisation and ATRX status was determined using immunohistochemical techniques. Tumours were grouped on the basis of molecular markers and outcomes compared. Results: The mean age of diagnosis was 42.6 years (20-73 years). There were 88 oligodendrogliomas (II = 47, III = 41), 18 diffuse astrocytomas (II = 9, III = 9) and 6 oligoastrocytomas (II = 4, III = 2). The majority of gliomas (87.5%) had mutations in IDH1/2. 1p/19q co-deletion was significantly associated with oligodendroglial morphology (p = < 0.001) and was mutually exclusive with ATRX mutation. Classification on the basis of molecular information showed a significant different in survival between the groups. Conclusions: ATRX immunohistochemisty is a useful adjunct which can be used with IDH mutation status, 1p/19q co-deletion and histological findings to further define tumour groups. More work is needed to understand the molecular profiles and prognostic implications for non co-deletion, ATRX preserved cases.

Static and dynamic 18F-FET PET for the characterization of gliomas defined by IDH and 1p/19q status.

PURPOSE: The molecular features isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion have gained major importance for both glioma typing and prognosis and have, therefore, been integrated in the World Health Organization (WHO) classification in 2016. The aim of this study was to characterize static and dynamic O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) PET parameters in gliomas with or without IDH mutation or 1p/19q co-deletion. METHODS: Ninety patients with newly diagnosed and untreated gliomas with a static and dynamic 18F-FET PET scan prior to evaluation of tumor tissue according to the 2016 WHO classification were identified retrospectively. Mean and maximum tumor-to-brain ratios (TBRmean/max), as well as dynamic parameters (time-to-peak and slope) of 18F-FET uptake were calculated. RESULTS: Sixteen (18%) oligodendrogliomas (IDH mutated, 1p/19q co-deleted), 27 (30%) astrocytomas (IDH mutated only), and 47 (52%) glioblastomas (IDH wild type only) were identified. TBRmean, TBRmax, TTP and slope discriminated between IDH mutated astrocytomas and IDH wild type glioblastomas (P < 0.01). TBRmean showed the best diagnostic performance (cut-off 1.95; sensitivity, 89%; specificity, 67%; accuracy, 81%). None of the parameters discriminated between oligodendrogliomas (IDH mutated, 1p/19q co-deleted) and glioblastomas or astrocytomas. Furthermore, TBRmean, TBRmax, TTP, and slope discriminated between gliomas with and without IDH mutation (p < 0.01). The best diagnostic performance was obtained for the combination of TTP with TBRmax or slope (accuracy, 73%). CONCLUSION: Data suggest that static and dynamic 18F-FET PET parameters may allow determining non-invasively the IDH mutation status. However, IDH mutated and 1p/19q co-deleted oligodendrogliomas cannot be differentiated from glioblastomas and astrocytomas by 18F-FET PET.

The 2016 revision of the WHO Classification of Central Nervous System Tumours: retrospective application to a cohort of diffuse gliomas.

The classification of central nervous system tumours has more recently been shaped by a focus on molecular pathology rather than histopathology. We re-classified 82 glial tumours according to the molecular-genetic criteria of the 2016 revision of the World Health Organization (WHO) Classification of Tumours of the Central Nervous System. Initial diagnoses and grading were based on the morphological criteria of the 2007 WHO scheme. Because of the impression of an oligodendroglial component on initial histological assessment, each tumour was tested for co-deletion of chromosomes 1p and 19q and mutations of isocitrate dehydrogenase (IDH-1 and 2) genes. Additionally, expression of proteins encoded by alpha-thalassemia X-linked mental retardation (ATRX) and TP53 genes was assessed by immunohistochemistry. We found that all but two tumours could be assigned to a specific category in the 2016 revision. The most common change in diagnosis was from oligoastrocytoma to specifically astrocytoma or oligodendroglioma. Analysis of progression free survival (PFS) for WHO grade II and III tumours showed that the objective criteria of the 2016 revision separated diffuse gliomas into three distinct molecular categories: chromosome 1p/19q co-deleted/IDH mutant, intact 1p/19q/IDH mutant and IDH wild type. No significant difference in PFS was found when comparing IDH mutant grade II and III tumours suggesting that IDH status is more informative than tumour grade. The segregation into distinct molecular sub-types that is achieved by the 2016 revision provides an objective evidence base for managing patients with grade II and III diffuse gliomas based on prognosis.

Non-invasive genotype prediction of chromosome 1p/19q co-deletion by development and validation of an MRI-based radiomics signature in lower-grade gliomas.

PURPOSE: To perform radiomics analysis for non-invasively predicting chromosome 1p/19q co-deletion in World Health Organization grade II and III (lower-grade) gliomas. METHODS: This retrospective study included 277 patients histopathologically diagnosed with lower-grade glioma. Clinical parameters were recorded for each patient. We performed a radiomics analysis by extracting 647 MRI-based features and applied the random forest algorithm to generate a radiomics signature for predicting 1p/19q co-deletion in the training cohort (n = 184). The clinical model consisted of pertinent clinical factors, and was built using a logistic regression algorithm. A combined model, incorporating both the radiomics signature and related clinical factors, was also constructed. The receiver operating characteristics curve was used to evaluate the predictive performance. We further validated the predictability of the three developed models using a time-independent validation cohort (n = 93). RESULTS: The radiomics signature was constructed as an independent predictor for differentiating 1p/19q co-deletion genotypes, which demonstrated superior performance on both the training and validation cohorts with areas under curve (AUCs) of 0.887 and 0.760, respectively. These results outperformed the clinical model (AUCs of 0.580 and 0.627 on training and validation cohorts). The AUCs of the combined model were 0.885 and 0.753 on training and validation cohorts, respectively, which indicated that clinical factors did not present additional improvement for the prediction. CONCLUSION: Our study highlighted that an MRI-based radiomics signature can effectively identify the 1p/19q co-deletion in histopathologically diagnosed lower-grade gliomas, thereby offering the potential to facilitate non-invasive molecular subtype prediction of gliomas.

The role of clinical and molecular factors in low-grade gliomas: what is their impact on survival?

AIM: To evaluate relevance of clinical and molecular factors in adult low-grade gliomas (LGG) and to correlate with survival. METHODS: We reviewed records from adult LGG patients from 1991 to 2015 who received surgery and had sufficient tissue to molecular biomarkers characterization. RESULTS: 213 consecutive LGG patients were included: 17.4% were low-risk, according to Radiation Therapy Oncology Group (RTOG) risk assessment. IDH 1/2 mutation, 1p/19q co-deletion, MGMT methylation were found in 93, 50.8 and 65.3% of patients. Median follow-up was 98.3 months. In univariate analysis, overall survival was influenced by extent of resection (p = 0.011), IDH mutation (p < 0.001), 1p/19q co-deletion (p = 0.015) and MGMT methylation (p = 0.013). In multivariate analysis, RTOG clinical risk (p = 0.006), IDH mutation (p < 0.001) and 1p/19q co-deletion (p = 0.035) correlated with overall survival. RTOG clinical risk (p = 0.006), IDH mutation (p < 0.001) and 1p/19q co-deletion (p = 0.035) correlated with overall survival. CONCLUSION: Both clinical and molecular factors are essential to determine prognosis and treatment strategies.

Gliosarcoma arising from oligodendroglioma (Oligosarcoma): A case report with genetic analyses.

Gliosarcomas are a type of bimorphic tumor composed of glial and sarcomatous elements, and are considered to be a variant of glioblastoma, WHO grade IV. To date, only rare cases of gliosarcoma with oligodendroglial components (oligosarcoma) have been reported. We report a case of oligosarcoma consisting of gliosarcoma arising from recurrent oligodendroglioma. A 53-year-old man, who had undergone a gross total resection of oligodendroglioma (WHO grade II) 11 years earlier, presented with a local tumor recurrence. The patient underwent a second gross total resection, whereupon a histopathological examination further revealed residual features of classical oligodendroglioma, and newly-developed sarcomatous characteristics. Both the primary and recurrent tumors showed 1p/19q co-deletion and mutation of the isocitrate dehydrogenase 1 (IDH1) gene, consistent with being oligodendroglial in nature. Loss of heterozygosity (LOH) of chromosome 1p/19q and IDH1 mutation have seldom been analyzed in previous reports of oligosarcomas. We report a rare case study supported by the results of genetic analyses. Our analyses have revealed that the sarcomatous component represents a metaplastic change occurring in the oligodendroglial element.

MGMT promoter methylation and 1p/19q co-deletion of surgically resected pulmonary carcinoid and large-cell neuroendocrine carcinoma.

BACKGROUND: The response to temozolomide (TMZ) treatment in small-cell lung cancer (SCLC) correlated with O(6)-methylguanine -DNA methyltransferase (MGMT) promoter methylation. 1p/19q co-deletion within oligodendroglioma is a responsive predictor for TMZ. Currently, the status of MGMT promoter methylation and 1p/19q co-deletion in pulmonary carcinoid (PC) and large-cell neuroendocrine carcinoma (LCNEC) is not reported. METHODS: Nine PC [two atypical carcinoids (AC), seven typical carcinoids (TC)] and six LCNEC patients were collected retrospectively. The pyrosequencing and fluorescence in situ hybridization were used to detect the MGMT promoter methylation and 1p/19q co-deletion in surgically resected specimens. Kaplan-Meier analysis was used to assess the rate of disease-free survival (DFS). RESULTS: MGMT promoter methylation was found in two (2/6, 15.3%) LCNEC patients but not in any PC patients. Three (3/6, 50%) 1p and two (2/6, 33.3%) 19q single deletions were found in LCNEC patients. One 1p single deletion was found in AC patients. One (1/7, 14.3%) 1p and two (2/7, 28.6%) 19q single deletions were found in TC patients. After a median follow-up of 38 months, three LCNEC patients developed distant metastasis and one patient died of LCNEC disease. The DFS of PC patients was much longer than LCNEC patients (χ 2 = 7.565, P = 0.006). CONCLUSIONS: MGMT promoter methylation and 1p/19q co-deletion might not be the ideal biomarkers for TMZ treatment in TC/AC patients. Thus, the detection of MGMT promoter methylation and whether it can be used as a medication for TMZ in LCNEC patients necessitates investigation. Furthermore, 1p deletion could be a negative prognostic factor for LCNEC patients.

Diagnostic revision of 206 adult gliomas (including 40 oligoastrocytomas) based on ATRX, IDH1/2 and 1p/19q status.

The diagnosis of 206 low and high grade adult gliomas, including 40 oligoastrocytomas, was revised based on the immunohistochemical reactivity for the ATRX protein, IDH1/2 mutation status and 1p/19q chromosomal status. All oligodendrogliomas kept the initial diagnosis. Astrocytomas did not change diagnosis in 30 of 36 cases (83.3 %); four of 36 (11.1 %) cases were reclassified as oligodendroglioma, one (2.8 %) as DNT and the other (2.8 %) as reactive gliosis. Oligoastrocytomas changed diagnosis in 35 of 40 (87.5 %) cases, being reclassified 22 of 40 (55 %) as astrocytoma, 11 of 40 (27.5 %) as oligodendroglioma and two of 40 (5 %) as reactive gliosis. Four (10 %) remained unclassifiable. In one case only (2.5 %), the diagnosis of oligoastrocytoma could not be excluded since tumor astrocytes and tumor oligodendrocytes coexisted in mixed tumor areas. In the GBM tumor subgroup, GBMO disappeared because they were not substantiated by molecular genetics. Pilocytic astrocytomas retained ATRX expression. Loss of nuclear ATRX protein expression was strongly associated to IDH1/2 mutations (p = 0.0001) and mutually exclusive with total 1p/19q co-deletion (p = 0.0001). In astrocytic tumors, loss of immunoreactivity for the ATRX protein was significantly associated to the ALT phenotype (p = 0.0003). The constitutive ATRX expression in microglia/macrophages may be misleading, especially in the identification of an oligodendroglial tumor infiltration. Of paramount importance in the recognition of oligodendroglial and astrocytic tumor cells were the double immunostainings for ATRX/GFAP, ATRX/IDH1R132H, ATRX/Iba-1 and ATRX/CD68.

IDH mutant and 1p/19q co-deleted oligodendrogliomas: tumor grade stratification using diffusion-, susceptibility-, and perfusion-weighted MRI.

PURPOSE: Currently, isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion are proven diagnostic biomarkers for both grade II and III oligodendrogliomas (ODs). Non-invasive diffusion-weighted imaging (DWI), susceptibility-weighted imaging (SWI), and dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) are widely used to provide physiological information (cellularity, hemorrhage, calcifications, and angiogenesis) of neoplastic histology and tumor grade. However, it is unclear whether DWI, SWI, and DSC-PWI are able to stratify grades of IDH-mutant and 1p/19q co-deleted ODs. METHODS: We retrospectively reviewed the conventional MRI (cMRI), DWI, SWI, and DSC-PWI obtained on 33 patients with IDH-mutated and 1p/19q co-deleted ODs. Features of cMRI, normalized ADC (nADC), intratumoral susceptibility signals (ITSSs), normalized maxim CBV (nCBV), and normalized maximum CBF (nCBF) were compared between low-grade ODs (LGOs) and high-grade ODs (HGOs). Receiver operating characteristic curve and logistic regression were applied to determine diagnostic performances. RESULTS: HGOs tended to present with prominent edema and enhancement. nADC, ITSSs, nCBV, and nCBF were significantly different between groups (all P < 0.05). The combination of SWI and DSC-PWI for grading resulted in sensitivity and specificity of 100.00 and 93.33%, respectively. CONCLUSIONS: IDH-mutant and 1p/19q co-deleted ODs can be stratified by grades using cMRI and advanced magnetic resonance imaging techniques including DWI, SWI, and DSC-PWI. Combined ITSSs with nCBV appear to be a promising option for grading molecularly defined ODs in clinical practice.

Treatment Outcomes in 1p19q Co-deleted/Partially Deleted Gliomas.

BACKGROUND: Radiotherapy with procarbazine, lomustine, and vincristine improves overall survival (OS) in patients with 1p19q co-deleted anaplastic oligodendroglioma/anaplastic oligoastrocytoma. METHODS: This retrospective analysis investigated outcomes in patients with 1p19q co-deleted/partially deleted oligodendroglioma, oligoastrocytoma, anaplastic oligodendroglioma, or anaplastic oligoastrocytoma. OS and progression-free survival (PFS) were analyzed using the Kaplan-Meier method and prognostic factors using the Cox proportional hazard model. RESULTS: A total of 106 patients (between December 1997 and December 2013) were included. Median age was 40 years (19-66), 58 were male (55%), Eastern Cooperative Oncology Group performance status was 0 in 80 patients (75%). 1p19q status was co-deleted in 66 (62%), incompletely co-deleted in 27 (25%), and 1p or 19q loss alone in four (4%) and nine (8%) patients, respectively. Isocitrate dehydrogenase-1 R132H mutation was found in 67 of 85 patients with sufficient material. Upfront treatment was given in 72 (68%) patients and temozolomide alone in 52 (49%). Median time to radiotherapy in 47 patients (44%) was 34.7 months and 41.2 months in 9 patients with co-deleted/incompletely co-deleted anaplastic oligodendroglioma/anaplastic oligoastrocytoma who received upfront temozolomide alone. Median OS was not reached and 5-year OS was 91% for all groups (median follow-up, 5.1 years). On multivariable analysis for all patients, receipt of therapy upfront versus none (p=0.04), PS 1 versus 0 (p<0.001) and 1p19q co-deletion/incomplete deletion versus 1p or 19q loss alone (p=0.005) were prognostic for PFS. Isocitrate dehydrogenase-1 status was not prognostic for PFS. CONCLUSIONS: With similar survival patterns in low-grade/anaplastic gliomas, molecular characteristics may be more important than histological grade. Longer follow-up and results of prospective trials are needed for definitive guidance on treatment of these patients.

Utility of ATRX immunohistochemistry in diagnosis of adult diffuse gliomas.

AIMS: We performed an immunohistochemical analysis of alpha-thalassaemia/mental retardation syndrome X-linked (ATRX) expression in adult diffuse gliomas, with reference to clinicopathological and genetic features, to determine the utility of this analysis in diagnostic practice. METHODS AND RESULTS: A total of 193 adult diffuse gliomas underwent immunohistochemical analysis. In areas in which internal controls, neurones, glia and blood vessels were properly stained, the ATRX immunoreactivity of tumour cells was either almost totally absent or completely retained in all cases. There was perfect concordance between the immunohistochemical results and ATRX mutation status, which was known in 19 cases. ATRX loss was observed in 54.5, 30.8 and 0.0% of grades II/III astrocytomas, oligoastrocytomas and oligodendrogliomas, respectively, and 12.7% of glioblastomas. In grades II/III gliomas, most ATRX-loss cases (92.3%) had IDH1/2 mutations. ATRX loss was associated significantly with TP53 mutation and p53 overexpression (P < 0.001), but was never accompanied by 1p/19q co-deletion. IDH1/2 mutation in ATRX-loss tumours was less frequent in glioblastomas than in grades II/III gliomas (P < 0.001). Further, there was no significant association between ATRX loss and p53 overexpression in glioblastomas. ATRX-loss glioblastomas affected younger patients (P < 0.001) and occurred more frequently in locations other than the cerebral hemispheres (P = 0.006). Most grades II/III gliomas (93.3%) were categorized into three molecular subtypes based on the status of IDH1/2 mutation, ATRX immunohistochemistry and 1p/19q co-deletion. CONCLUSIONS: Distinct histological and molecular characteristics of adult diffuse gliomas with and without ATRX immunoreactivity indicate the utility of ATRX immunohistochemistry in diagnostic practice.