Spectrum of Findings Seen in Patients With IDH1/2-Mutant Cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma-with a growing incidence rate and poor prognosis-is not an aggressive tumor that is not uncommon. Molecular profiling can reveal actionable aberrations in at least a third of the tumors. This is especially so in the case of intrahepatic cholangiocarcinoma (ICC), where mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1/2) make up 15%-20% of these tumors. IDH1/2 mutant ICC is a rare disease that has not been adequately reported. To expand the spectrum of findings seen in these patients, we present a single institution case series. METHODS AND RESULTS: We descriptively characterize the clinical, radiological, and histopathological findings of 12 such patients. IDH1/2 mutant ICC was found in elderly women, with two-thirds of patients having additional co-mutations. Anecdotally, patients who did receive systemic and/or locoregional therapies had long-term durable outcomes. CONCLUSION: Our findings indicate an increasing need to personalize an approach for these patients with specific molecular alterations. With the advent of the IDH1 inhibitor ivosidenib and other inhibitors in this space, IDH1/2 mutation has both prognostic and predictive value. Our series builds upon the patterns and findings seen in these patients.

The Leukemic Isocitrate Dehydrogenase (IDH) 1/2 Mutations Impair Myeloid and Erythroid Cell Differentiation of Primary Human Hematopoietic Stem and Progenitor Cells (HSPCs).

How hematopoietic stem and progenitor cell (HSPC) fate decisions are affected by genetic alterations acquired during AML leukemogenesis is poorly understood and mainly explored in animal models. Here, we study isocitrate dehydrogenase (IDH) gene mutations in the human model of HSPC and discuss the available literature on this topic. IDH1/2 mutations occur in ~20% of AML cases, are recognized among the mutations earliest acquired during leukemogenesis, and are targets of specific inhibitors (ivosidenib and enasidenib, respectively). In order to investigate the direct effects of these mutations on HSPCs, we expressed IDH1-R132H or IDH2-R140Q mutants into human CD34+ healthy donor cells via lentiviral transduction and analyzed the colony-forming unit (CFU) ability. CFU ability was dramatically compromised with a complete trilineage block of differentiation. Strikingly, the block was reversed by specific inhibitors, confirming that it was a specific effect induced by the mutants. In line with this observation, the CD34+ leukemic precursors isolated from a patient with IDH2-mutated AML at baseline and during enasidenib treatment showed progressive and marked improvements in their fitness over time, in terms of CFU ability and propensity to differentiate. They attained clonal trilinear reconstitution of hematopoiesis and complete hematological remission.

Molecular Pathology of Gliomas.

Gliomas are the most common adult and pediatric primary brain tumors. Molecular studies have identified features that can enhance diagnosis and provide biomarkers. IDH1/2 mutation with ATRX and TP53 mutations defines diffuse astrocytomas, whereas IDH1/2 mutations with 1p19q loss defines oligodendroglioma. Focal amplifications of receptor tyrosine kinase genes, TERT promoter mutation, and loss of chromosomes 10 and 13 with trisomy of chromosome 7 are characteristic features of glioblastoma and can be used for diagnosis. BRAF gene fusions and mutations in low-grade gliomas and histone H3 mutations in high-grade gliomas also can be used for diagnostics.

The Cancer Driver Genes IDH1 and IDH2 and CD204 in WHO-Grade 4 Astrocytoma: Crosstalk Between Cancer Metabolism and Tumour Associated Macrophage Recruitment in Tumour Microenvironment.

Purpose: IDH1 and IDH2 are hotspot mutations commonly identified in WHO-grade 4 astrocytomas. Their association with TAMs has never been investigated. We aim to explore the crosstalk between the IDH1/2 mutation metabolic effect and TAMs in tumour microenvironment and how this relationship affects the tumour recurrence. Patients and Methods: The study included 20 samples of patients with WHO-grade 4 astrocytoma. The alteration hotspot in codon IDH1R132 and IDH2R172 was examined using direct sequencing. The protein expression of CD204 on TAM was detected through immunohistochemistry. Results: IDH1R132 and IDH2R172 were symmetrically identified as wildtype in 18/20 tumours (90%) and the remaining 2 tumours (10%) showed synonymous mutations on both codons. Tumours with IDH1/2-wildtype showed high expression of CD204+TAMs in 10 cases and low expression in 8 cases. Typical expression was seen equally in IDH1/2 mutant tumours. There was no significant association between IDH1/2 and CD204+TAM expression (p= 0.999). The association between the two groups was significantly observed among IDH-wildtype tumours (p=0.027). Highly expressed CD204 in IDH-wildtype tumours showed a median recurrence at 10 months compared to low CD204 expression, showed a median recurrence interval at 24 months. Conclusion: IDH1R132 or IDHR172 has the same impact on the classification and prognosis of WHO-grade 4 astrocytoma. There was no crosstalk between IDH1/2 metabolic effect and CD204+TAM. However, IDH-wildtype glioblastomas with dense CD204+TAM are associated with early recurrence. Because the sample size is small, a larger study is recommended to determine the impact of IDH1/2 on TAMs.

Multi-institutional study of the frequency, genomic landscape, and outcome of IDH-mutant glioma in pediatrics.

BACKGROUND: The incidence and biology of IDH1/2 mutations in pediatric gliomas are unclear. Notably, current treatment approaches by pediatric and adult providers vary significantly. We describe the frequency and clinical outcomes of IDH1/2-mutant gliomas in pediatrics. METHODS: We performed a multi-institutional analysis of the frequency of pediatric IDH1/2-mutant gliomas, identified by next-generation sequencing (NGS). In parallel, we retrospectively reviewed pediatric IDH1/2-mutant gliomas, analyzing clinico-genomic features, treatment approaches, and outcomes. RESULTS: Incidence: Among 851 patients with pediatric glioma who underwent NGS, we identified 78 with IDH1/2 mutations. Among patients 0-9 and 10-21 years old, 2/378 (0.5%) and 76/473 (16.1%) had IDH1/2-mutant tumors, respectively. Frequency of IDH mutations was similar between low-grade glioma (52/570, 9.1%) and high-grade glioma (25/277, 9.0%). Four tumors were graded as intermediate histologically, with one IDH1 mutation. Outcome: Seventy-six patients with IDH1/2-mutant glioma had outcome data available. Eighty-four percent of patients with low-grade glioma (LGG) were managed observantly without additional therapy. For low-grade astrocytoma, 5-year progression-free survival (PFS) was 42.9% (95%CI:20.3-63.8) and, despite excellent short-term overall survival (OS), numerous disease-related deaths after year 10 were reported. Patients with high-grade astrocytoma had a 5-year PFS/OS of 36.8% (95%CI:8.8-66.4) and 84% (95%CI:50.1-95.6), respectively. Patients with oligodendroglioma had excellent OS. CONCLUSIONS: A subset of pediatric gliomas is driven by IDH1/2 mutations, with a higher rate among adolescents. The majority of patients underwent upfront observant management without adjuvant therapy. Findings suggest that the natural history of pediatric IDH1/2-mutant glioma may be similar to that of adults, though additional studies are needed.

Measurable Residual Disease Monitoring by Locked Nucleic Acid Quantitative Real-Time PCR Assay for IDH1/2 Mutation in Adult AML.

Locked nucleic acid quantitative Real-Time PCR (LNA-qPCR) for IDH1/2 mutations in AML measurable residual disease (MRD) detection is rarely reported. LNA-qPCR was applied to quantify IDH1/2 mutants MRD kinetics in bone marrow from 88 IDH1/2-mutated AML patients, and correlated with NPM1-MRD, clinical characteristics, and outcomes. The median normalized copy number (NCN) of IDH1/2 mutants decreased significantly from 53,228 (range 87−980,686)/ALB × 106 at diagnosis to 773 (range 1.5−103,600)/ALB × 106 at first complete remission (CR). IDH1/2 LNA-qPCR MRD was concordant with remission status or NPM1-MRD in 79.5% (70/88) of patients. Younger patients and patients with FLT3 mutations had higher concordance. The Spearman correlation coefficient (rs) and concordance rate between the log reduction of IDH1/2 LNA-qPCR and NPM1-MRD were 0.68 and 81% (K = 0.63, 95% CI 0.50−0.74), respectively. IDH1/2-MRD > 2 log reduction at first CR predicted significantly better relapse-free survival (3-year RFS rates 52.9% vs. 31.9%, p = 0.007) and cumulative incidence of relapse (3-year CIR rates 44.5% vs. 64.5%, p = 0.012) compared to IDH1/2-MRD ≤ 2 log reduction. IDH1/2-MRD > 2 log reduction during consolidation is also associated with a significantly lower CIR rate than IDH1/2-MRD ≤ 2 log reduction (3-year CIR rates 42.3% vs. 68.8%, p = 0.019). LNA-qPCR for IDH1/2 mutation is a potential MRD technique to predict relapse in IDH1/2-mutated AML patients, especially for those with IDH1/2 MRD > 2 log reduction at first CR or a concurrent FLT3 mutation.

Early atypical malignant transformation of diffuse low-grade astrocytoma: The importance of genotyping.

Diffuse astrocytoma (WHO grade II) has classically been considered a slow growing tumour, typically affecting young adults, with tendency for late malignant conversion. We describe a case of early atypical malignant transformation of diffuse astrocytoma seventeen months after complete surgical removal, as an intraventricular high-grade glioma (HGG). Retrospective laboratory findings for the presence of IDH 1/2 (isocitrate dehydrogenase) mutations were negative. There is growing evidence that IDH-wildtype (wt) astrocytomas behave more aggressively, therefore identifying IDH-mutation status should be mandatory in order to determine disease prognosis and guide treatment course.

Molecular Pathology of Gliomas.

Gliomas are the most common adult and pediatric primary brain tumors. Molecular studies have identified features that can enhance diagnosis and provide biomarkers. IDH1/2 mutation with ATRX and TP53 mutations defines diffuse astrocytomas, whereas IDH1/2 mutations with 1p19q loss defines oligodendroglioma. Focal amplifications of receptor tyrosine kinase genes, TERT promoter mutation, and loss of chromosomes 10 and 13 with trisomy of chromosome 7 are characteristic features of glioblastoma and can be used for diagnosis. BRAF gene fusions and mutations in low-grade gliomas and histone H3 mutations in high-grade gliomas also can be used for diagnostics.

Improving performance and generalizability in radiogenomics: a pilot study for prediction of IDH1/2 mutation status in gliomas with multicentric data.

Purpose: Radiogenomics offers a potential virtual and noninvasive biopsy. However, radiogenomics models often suffer from generalizability issues, which cause a performance degradation on unseen data. In MRI, differences in the sequence parameters, manufacturers, and scanners make this generalizability issue worse. Such image acquisition information may be used to define different environments and select robust and invariant radiomic features associated with the clinical outcome that should be included in radiomics/radiogenomics models. Approach: We assessed 77 low-grade gliomas and glioblastomas multiform patients publicly available in TCGA and TCIA. Radiomics features were extracted from multiparametric MRI images (T1-weighted, contrast-enhanced T1-weighted, T2-weighted, and fluid-attenuated inversion recovery) and different regions-of-interest (enhancing tumor, nonenhancing tumor/necrosis, and edema). A method developed to find variables that are part of causal structures was used for feature selection and compared with an embedded feature selection approach commonly used in radiomics/radiogenomics studies, across two different scenarios: (1) leaving data from a center as an independent held-out test set and tuning the model with the data from the remaining centers and (2) use stratified partitioning to obtain the training and the held-out test sets. Results: In scenario (1), the performance of the proposed methodology and the traditional embedded method was AUC: 0.75 [0.25; 1.00] versus 0.83 [0.50; 1.00], Sens.: 0.67 [0.20; 0.93] versus 0.67 [0.20; 0.93], Spec.: 0.75 [0.30; 0.95] versus 0.75 [0.30; 0.95], and MCC: 0.42 [0.19; 0.68] versus 0.42 [0.19; 0.68] for center 1 as the held-out test set. The performance of both methods for center 2 as the held-out test set was AUC: 0.64 [0.36; 0.91] versus 0.55 [0.27; 0.82], Sens.: 0.00 [0.00; 0.73] versus 0.00 [0.00; 0.73], Spec.: 0.82 [0.52; 0.94] versus 0.91 [0.62; 0.98], and MCC: - 0.13 [ - 0.38 ; - 0.04 ] versus - 0.09 [ - 0.38 ; - 0.02 ] , whereas for center 3 was AUC: 0.80 [0.62; 0.95] versus 0.89 [0.56; 0.96], Sens.: 0.86 [0.48; 0.97] versus 0.86 [0.48; 0.97], Spec.: 0.72 [0.54; 0.85] versus 0.79 [0.61; 0.90], and MCC: 0.47 [0.41; 0.53] versus 0.55 [0.48; 0.60]. For center 4, the performance of both methods was AUC: 0.77 [0.51; 1.00] versus 0.75 [0.47; 0.97], Sens.: 0.53 [0.30; 0.75] versus 0.00 [0.00; 0.15], Spec.: 0.71 [0.35; 0.91] versus 0.86 [0.48; 0.97], and MCC: 0.23 [0.16; 0.31] versus. - 0.32 [ - 0.46 ; - 0.20 ] . In scenario (2), the performance of these methods was AUC: 0.89 [0.71; 1.00] versus 0.79 [0.58; 0.94], Sens.: 0.86 [0.80; 0.92] versus 0.43 [0.15; 0.74], Spec.: 0.87 [0.62; 0.96] versus 0.87 [0.62; 0.96], and MCC: 0.70 [0.60; 0.77] versus 0.33 [0.24; 0.42]. Conclusions: This proof-of-concept study demonstrated good performance by the proposed feature selection method in the majority of the studied scenarios, as it promotes robustness of features included in the models and the models' generalizability by making used imaging data of different scanners or with sequence parameters.

Lactonization of the Oncometabolite D-2-Hydroxyglutarate Produces a Novel Endogenous Metabolite.

In recent years, onco-metabolites like D-2-hydroxyglutarate, which is produced in isocitrate dehydrogenase-mutated tumors, have gained increasing interest. Here, we report a metabolite in human specimens that is closely related to 2-hydroxyglutarate: the intramolecular ester of 2-hydroxyglutarate, 2-hydroxyglutarate-γ-lactone. Using 13C5-L-glutamine tracer analysis, we showed that 2-hydroxyglutarate is the endogenous precursor of 2-hydroxyglutarate-lactone and that there is a high exchange between these two metabolites. Lactone formation does not depend on mutated isocitrate dehydrogenase, but its formation is most probably linked to transport processes across the cell membrane and favored at low environmental pH. Furthermore, human macrophages showed not only striking differences in uptake of 2-hydroxyglutarate and its lactone but also in the enantiospecific hydrolysis of the latter. Consequently, 2-hydroxyglutarate-lactone may play a critical role in the modulation of the tumor microenvironment.

[Histomolecular diagnosis of glial and glioneuronal tumours]. / Le diagnostic histo-moléculaire des tumeurs gliales et glioneuronales.

While rare compared to extra-cranial neoplasms, glial and glioneuronal tumors are responsible of high morbidity and mortality. In 2016, the World Health Organization introduced histo-molecular ("integrated") diagnostics for central nervous system tumors based on morphology, immunohistochemistry and the presence of key genetic alterations. This combined phenotypic-genotypic classification allows for a more objective diagnostic of brain tumors. The implementation of such a classification in daily practice requires immunohistochemical surrogates to detect common genetic alterations and sometimes expensive and not widely available molecular biology techniques. The first step in brain tumor diagnostics is to inquire about the clinical picture and the imaging findings. When dealing with a glial tumor, the pathologist needs to assess its nature, infiltrative or circumscribed. If the tumor is infiltrative, IDH1/2 genes (prognostic marker) and chromosomes 1p/19q (diagnosis of oligodendroglioma) need to be assessed. If the tumor appears circumscribed, the pathologist should look for a neuronal component associated with the glial component (glioneuronal tumor). A limited immunohistochemistry panel will help distinguish between diffuse glioma (IDH1-R132H, ATRX, p53) and circumscribed glial/glioneuronal tumor (CD34, neuronal markers, BRAF-V600E), and some antibodies may reliably detect genetic alterations (IDH1-R132H, BRAF-V600E and H3-K27M mutations). Chromosomal imbalances (1p/19q codeletion in oligodendroglioma; chromosome 7 gain/chromosome 10 loss and EGFR amplification in glioblastoma) and gene rearrangements (BRAF fusion, FGFR1 fusion) will be identified by molecular biology techniques. The up-coming edition of the WHO classification of the central nervous system tumors will rely more heavily on molecular alterations to accurately diagnose and treat brain tumors.

Early atypical malignant transformation of diffuse low-grade astrocytoma: The importance of genotyping.

Diffuse astrocytoma (WHO grade II) has classically been considered a slow growing tumour, typically affecting young adults, with tendency for late malignant conversion. We describe a case of early atypical malignant transformation of diffuse astrocytoma seventeen months after complete surgical removal, as an intraventricular high-grade glioma (HGG). Retrospective laboratory findings for the presence of IDH 1/2 (isocitrate dehydrogenase) mutations were negative. There is growing evidence that IDH-wildtype (wt) astrocytomas behave more aggressively, therefore identifying IDH-mutation status should be mandatory in order to determine disease prognosis and guide treatment course.

Distinct clinical and prognostic implication of IDH1/2 mutation and other most frequent mutations in large duct and small duct subtypes of intrahepatic cholangiocarcinoma.

BACKGROUND: Isocitrate dehydrogenase 1/2 (IDH1/2), BAP1, ARID1A and PBRM1 have been reported as the most frequent mutant genes in intrahepatic cholangiocarcinoma (ICC), and their relationships with clinicopathological features and prognosis were researched in this study. METHODS: We collected clinical data of 130 ICC patients from January 2012 to December 2017. The IDH1/2 mutation and loss of BAP1, ARID1A and PBRM1 expressions were detected by DNA sequencing or immunohistochemical methods, and histological subtype of ICCs was determined by hematoxylin-eosin, Alcian blue and S100P staining. RESULTS: IDH1/2 mutation was related to decreased preoperative serum total bilirubin (P = 0.039), ferritin (P = 0.000) and higher histological differentiation (P = 0.024), and was associated with prolonged disease-free survival (P = 0.009) and a trend toward increased overall survival (P = 0.126) in small duct type of ICCs. Immunohistochemical staining results of MsMab-1 were generally consistent with DNA sequencing for IDH1/2 mutant in ICCs (κ = 0.691). Only BAP1 expression loss was correlated to prolonged disease-free survival (P = 0.031) and overall survival (P = 0.041) in large duct type of ICCs. CONCLUSIONS: IDH1/2 mutation is a favorable predictor and may be related to iron metabolism in small duct type of ICCs. Furthermore, we suggest that the detection of IDH1/2 mutation is indispensable to determine targeted therapy in small duct type ICCs, while it is not necessary in large duct of ICCs. MsMab-1 is a relatively effective multi-specific antibody against IDH1/2 mutant in ICCs. BAP1 expression loss was correlated with improved prognosis only in large duct type ICCs.

MGMT gene promoter methylation and its correlation with clinicopathological parameters in glioblastomas.

BACKGROUND: MGMT (O6-methyl guanine DNA methyl transferase) promoter hypermethylation is a prognostic and predictive biomarker for glioblastomas (GBM). AIMS: To evaluate the frequency of MGMT methylation status in a single institute series of 134 GBMs and correlate it with clinical (age, sex, location, survival) and other molecular parameters [such as p53 expression, alpha thalassemia/mental retardation syndrome X-linked (ATRX) expression, isocitrate dehydrogenase (IDH) 1R132H mutation, and epidermal growth factor receptor (EGFR) gene amplification]. RESULTS: One hundred and thirty-four GBMs were evaluated by methylation-specific polymerase chain reaction (MSP) for MGMT promoter methylation status. The results were correlated with the above mentioned clinicopathological parameters. MGMT gene promoter methylation was identified in 49.2% (66/134) GBMs, and was significantly associated with IDH1R132H mutation (14/66; 21%; P - value, 0.01) and ATRX loss (15/66; 23%; P - value, 0.01). Confluent necrosis was found to be significantly associated with MGMT unmethylation status (P - value: 0.002). Multivariable logistic regression analysis showed confluent necrosis as a single independent predictor (odds ratio [OR], 2.5; confidence interval [CI], 1.0-5.8; P - value, 0.04) of MGMT unmethylation status among all the parameters studied. CONCLUSIONS: The frequency of MGMT promoter methylation in GBMs was 49.2%, which was significantly associated with IDHR132H mutation and ATRX loss. In addition, the presence of confluent necrosis was significantly associated with MGMT unmethylation and was found to be an independent predictor of the same.

IDH1/2 Mutations Predict Shorter Survival in Chondrosarcoma.

Background. Recent studies have shown that isocitrate dehydrogenase 1/2 (IDH1/2)- activating mutations occur in a variety of cancers, including acute myeloid leukaemia, gliomas, and chondrosarcomas (CHS)s. The effect of IDH1/2 mutation on overall survival (OS) has not been reported in CHS. The aim of our study was to assess the prevalence of known cancer-related gene mutations in CHS, as well as their prognostic role in patient survival. Methods. DNA from FFPE samples of 80 patients (F:M- 1:1.3; mean age: 58 years; range 27-86) with histologically confirmed CHS (G1:29; G2:34; G3:17) was subjected to library preparation with the Ion AmpliSeq Cancer Hotspot Panel v2 and sequenced on the PGM Ion Torrent. Results. Among the clinical features only histological grade influenced OS. Deep sequencing identified 1784 single nucleotide variants. Of them, 426 were considered to be pathogenic or probably pathogenic. Activating IDH1/2 mutations were found in 27 patients (34%) including 17 R132 IDH1 (21%), 10 R172 IDH2 (13%) and 3 R140 IDH2 variants (4%). Three patients had concurrent IDH1 and IDH2 mutations. The R140 IDH2 mutant has not been reported to date in CHS patients. OS for CHS patients with IDH1/2 mutations was significantly lower than in patients without mutations (93% vs 64%; p<0.001). No other genetic feature of the Cancer Hotspot Panel had an impact on OS. Conclusions. In CHS, IDH1/2-mutation status and the histological aggressiveness of the CHS are important predictors for OS. The R140 IDH2 may also be a novel target for the treatment of CHS patients.

Oncogenic transgelin-2 is differentially regulated in isocitrate dehydrogenase wild-type vs. mutant gliomas.

The presence of an isocitrate dehydrogenase (IDH1/2) mutation in gliomas is associated with favorable outcomes compared to gliomas without the mutation (IDH1/2 wild-type, WT). The underlying biological mechanisms accounting for improved clinical outcomes in IDH1/2 mutant gliomas remain poorly understood, but may, in part, be due to the glioma CpG island methylator phenotype (G-CIMP) and epigenetic silencing of genes. We performed profiling of IDH1/2 WT versus IDH1/2 mutant Grade II and III gliomas and identified transgelin-2 (TAGLN2), an oncogene and actin-polymerizing protein, to be expressed at significantly higher levels in IDH1/2 WT gliomas compared to IDH1/2 mutant gliomas. This differential expression of TAGLN2 was primarily due to promoter hypermethylation in IDH1/2 mutant gliomas, suggesting involvement of TAGLN2 in the G-CIMP. Our results also suggest that TAGLN2 may be involved in progression due to higher expression in glioblastomas compared to IDH1/2 WT gliomas of lower grades. Furthermore, our results suggest that TAGLN2 functions as an oncogene by contributing to proliferation and invasion when overexpressed in IDH1/2 WT glioma cells. Taken together, this study demonstrates a possible link between increased TAGLN2 expression, invasion and poor patient outcomes in IDH1/2 WT gliomas and identifies TAGLN2 as a potential novel therapeutic target for IDH1/2 WT gliomas.

Identification of time-to-peak on dynamic 18F-FET-PET as a prognostic marker specifically in IDH1/2 mutant diffuse astrocytoma.

Background: Stratification of glioma according to isocitrate dehydrogenase 1/2 (IDH1/2) mutation and 1p/19q codeletion status has gained major importance in the new World Health Organization (WHO) classification. Parameters derived from uptake dynamics of 18F-fluoro-ethyl-tyrosine PET (18F-FET-PET) such as minimal time-to-peak (TTPmin) allow discrimination between different prognostic glioma subgroups, too. The present study is aimed at exploring whether TTPmin analysis provides prognostic information beyond the WHO classification. Methods: Three hundred patients with newly diagnosed WHO 2007 grades II-IV gliomas with 18F-FET-PET imaging at diagnosis were grouped into 4 subgroups (IDH1/2 mut-1p/19q codel; IDH1/2 mut-1p/19q non-codel; IDH1/2 wildtype WHO grade II and III tumors; and glioblastoma). Clinical and imaging factors such as age, Karnofsky performance score, treatment, TTPmin, and maximal tumor-to-brain ratio (TBRmax) were analyzed with regard to progression-free and overall survival (PFS and OS) via univariate and multivariate regression analysis. Results: PFS and OS were longest in the IDH1/2 mut-1p/19q codel subgroup, followed by IDH1/2 mut-1p/19q non-codel, IDH1/2 wildtype, and GBM (P < 0.001). Further, outcome stratified by TTPmin with a cutoff of 17.5 minutes revealed significantly longer PFS and OS in patients with TTPmin >17.5 minutes (P < 0.001 for PFS and OS). Lower TBRmax values or the absence of 18F-FET uptake was also associated with favorable outcome in the entire group. In the subgroup analyses, longer median TTPmin was associated with improved outcome specifically in the IDH1/2 mut-1p/19q non-codel group. Conclusion: 18F-FET-PET-derived dynamic analysis defines prognostically distinct subgroups of IDH1/2 mutant-1p/19q non-codel gliomas which cannot be distinguished as yet by molecular marker analysis.

Expression and prognostic value of microRNAs in lower-grade glioma depends on IDH1/2 status.

Histological and genomic characteristics are widely used in glioma management and research. This study investigated their relationship to the expression and prognostic value of microRNAs (miRNAs) in lower-grade glioma (LGG). A total of 447 LGG samples with available clinical and genomic information from The Cancer Genome Atlas database were reviewed. Samples with isocitrate dehydrogenase (IDH) 1/2 mutations (n = 366) were randomly divided into training and validation sets to establish and confirm a four-miRNA-based risk classifier. We found that IDH1/2 mutation status had greater impact than histological and other genomic features on miRNA expression patterns; 361/487 (74%) of miRNAs were differentially expressed according to IDH1/2 mutation status. Importantly, there were no miRNAs with the same prognostic significance among groups with different IDH1/2 mutation status. For IDH1/2-mut LGG, a four-miRNA risk classifier (miR-10b, miR-130b, miR-1304, and miR-302b) was established that could independently distinguish cases as high or low risk of poor prognosis in both training and validation sets. The risk classifier outperformed individual miRNAs and traditional prognostic factors in terms of sensitivity and specificity. Bioinformatic analyses indicated that high-risk samples were more mitotically active than low-risk samples. Taken together, IDH1/2 mutation status had a significant influence on miRNA expression and prognostication in LGG. The four-miRNA-based risk classifier can be used for risk stratification of IDH1/2-mut LGG.

Prognostic impact of the 2016 WHO classification of diffuse gliomas in the French POLA cohort.

The new WHO classification of diffuse gliomas has been refined and now includes the 1p/19q codeletion, IDH1/2 mutation, and histone H3-K27M mutation. Our objective was to assess the prognostic value of the updated 2016 WHO classification in the French POLA cohort. All cases of high-grade oligodendroglial tumors sent for central pathological review and included into the French nationwide POLA cohort were reclassified according to the updated 4th WHO classification. In total, 1041 patients were included, with a median age at diagnosis of 50.4 years (range 17.1-84.4). Based on the new histomolecular classification, diagnoses included anaplastic oligodendroglioma IDH mutant and 1p/19q-codeleted (32.5 %), anaplastic astrocytoma IDH mutant (IDH (mut)) (11.0 %), anaplastic astrocytoma IDH wild type (IDH (wt)) (5.3 %), glioblastoma IDH (mut) (17.1 %), and glioblastoma IDH (wt) (33.2 %). Ten patients presented with a diffuse midline tumor, H3 K27M mutant. The new WHO classification was prognostic for progression-free survival (PFS) and overall survival (OS) (p < 0.001). We did not find prognosis differences between grades III and IV for IDH (mut) 1p/19q intact and IDH (wt) gliomas in univariate and multivariate analyses. Among anaplastic astrocytoma IDH (wt), cases with chromosome arm 7p gain and 10q loss (55 %) had shorter PFS than the others (p = 0.027). In conclusion, the new WHO histomolecular classification of diffuse gliomas presented with high prognostic value. Grading was not discriminant between grade III and IV high-grade gliomas.