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Simple Summary: Mutations in the telomerase reverse transcriptase (TERT) gene promoter are rare in meningiomas, but are associated with more aggressive forms of meningiomas as well as recurrence and progression. In this study, we analyzed data of patients who underwent meningioma surgery with neuropathologically assessed TERT promoter mutation status. Semiautomatic segmentation of the meningiomas was performed on preoperative magnetic resonance imaging (MRI). Radiomics features were extracted from T1-weighted contrast-enhanced MRI data. TERT promoter mutations were predicted using the random forest algorithm with an increasing number of radiomic features. 117 image sets were included and divided into a training group with 94 image sets and a test group with 23 image sets. Based on the test group, established five- and eight-feature models demonstrated high sensitivity, specificity, accuracy and AUC values for prediction of TERT promoter mutation status. Purpose: In meningiomas, TERT promotor mutations are rare but qualify the diagnosis of anaplasia, directly impacting adjuvant therapy. Effective screening for patients at risk for promotor mutations could enable more targeted molecular analyses and improve diagnosis and treatment. Methods: Semiautomatic segmentation of intracranial grade 2/3 meningiomas was performed on preoperative magnetic resonance imaging. Discriminatory power to predict TERT promoter mutations was analyzed using a random forest algorithm with an increasing number of radiomic features. Two final models with five and eight features with both fixed and differing radiomics features were developed and adjusted to eliminate random effects and to avoid overfitting. Results: A total of 117 image sets including training (N = 94) and test data (N = 23) were analyzed. To eliminate random effects and demonstrate the robustness of our approach, data partitioning and subsequent model development and testing were repeated a total of 100 times (each time with repartitioned training and independent test data). The established five- and eight-feature models with both fixed and different radiomics features enabled the prediction of TERT with similar but excellent performance. The five-feature (different/fixed) model predicted TERT promotor mutation status with a mean AUC of 91.8%/94.3%, mean accuracy of 85.5%/88.9%, mean sensitivity of 88.6%/91.4%, mean specificity of 83.2%/87.0%, and a mean Cohen's Kappa of 71.0%/77.7%. The eight-feature (different/fixed) model predicted TERT promotor mutation status with a mean AUC of 92.7%/94.6%, mean accuracy of 87.3%/88.9%, mean sensitivity of 89.6%/90.6%, mean specificity of 85.5%/87.5%, and a mean Cohen's Kappa of 74.4%/77.6%. Of note, the addition of further features of up to N = 8 only slightly increased the performance. Conclusions: Radiomics-based machine learning enables prediction of TERT promotor mutation status in meningiomas with excellent discriminatory performance. Future analyses in larger cohorts should include grade 1 lesions as well as additional molecular alterations. [ABSTRACT FROM AUTHOR]

The World Health Organization (WHO) classification and grading system attempts to predict the clinical course of meningiomas based on morphological parameters. However, because of high interobserver variation of some criteria, more reliable prognostic markers are required. Here, we assessed the TERT promoter for mutations in the hotspot regions C228T and C250T in meningioma samples from 252 patients. Mutations were detected in 16 samples (6.4% across the cohort, 1.7%, 5.7%, and 20.0% of WHO grade I, II, and III cases, respectively). Data were analyzed by t test, Fisher's exact test, log-rank test, and Cox proportional hazard model. All statistical tests were two-sided. Within a mean follow-up time in surviving patients of 68.1 months, TERT promoter mutations were statistically significantly associated with shorter time to progression (P < .001). Median time to progression among mutant cases was 10.1 months compared with 179.0 months among wild-type cases. Our results indicate that the inclusion of molecular data (ie, analysis of TERT promoter status) into a histologically and genetically integrated classification and grading system for meningiomas increases prognostic power. Consequently, we propose to incorporate the assessment of TERT promoter status in upcoming grading schemes for meningioma. [ABSTRACT FROM AUTHOR]

Hot spot mutations in the promoter region of telomerase reverse transcriptase ( TERT) have recently been described in several human tumor entities. These mutations result in an upregulation of the telomerase complex activity and thus constitute a relevant mechanism for immortalization of tumor cells. Knowledge of the TERT promoter status in tumors is likely to be of interest for molecular classification and as a potential target for therapy. We, therefore, performed a systematic analysis of TERT promoter mutations in 1,515 tumors of the human nervous system and its coverings including 373 pediatric and 1,142 adult patients. We detected a total of 327 mutations. TERT promoter mutations were exceedingly rare in tumors typically encountered in pediatric patients. In entities typically encountered in adult patients TERT promoter mutations were strongly associated with older age ( p < 0.0001). Highest mutation frequencies were detected in gliosarcomas (81 %), oligodendrogliomas (78 %), oligoastrocytomas (58 %), primary glioblastomas (54 %), and solitary fibrous tumors (50 %). Related to other molecular alterations, TERT promoter mutations were strongly associated with 1p/19q loss ( p < 0.0001), but inversely associated with loss of ATRX expression ( p < 0.0001) and IDH1/IDH2 mutations ( p < 0.0001). TERT promoter mutations are typically found in adult patients and occur in a highly tumor type-associated distribution. [ABSTRACT FROM AUTHOR]

Introduction: Klippel-Feil syndrome (KFS) is considered a rare developmental disorder characterized by mono- or multisegmental fusion of the cervical vertebrae which is frequently associated with diverse non-osseous, e.g. neural, visceral, cardiopulmonary and genitourinary development anomalies. Anterior cervical meningomyelocele (MMC) in KFS has only been described in two previous patients, both with non-surgical treatment. Clnical presentation: We present the case of a 26-year-old female suffering from KFS, presenting with progressive bilateral C6 paraesthesias, C7 and C8 motor weakness and myelopathy. Radiological imaging revealed incomplete osseous fusion of the vertebrae C2-Th1. The spinal cord was displaced ventro-caudally through a large anterior MMC, apparently fixed at the dorsal oesophagus, severely stretching the cervical nerve roots. Surgery was indicated due to progression of the symptoms and was performed through a combined partial sternotomy and ventral anterolateral cervical approach. Intraoperatively, both division of oesophago-dural adhesions and intradural untethering of adhesions of the myelon with caudal parts of the cele were performed. Evoked somatosensory potentials improved immediately and 6-day postoperative MRI revealed a nearly complete reposition of the spinal cord in its physiological position. Genetic sequence analyses ruled out mutation of the growth and differentiation factor 6 (GDF6). Apart from slight intermittent paraesthesia, symptoms resolved almost completely within weeks after operation. Both radiological and neurological improvement remained stable at 16 months of follow-up. Conclusion: KFS with anterior cervical MMC is rarely seen and may require surgery in case of clincial signs of nerve root compression or myelopathy. Osseous decompression, untethering and adhesiolysis under electrophysiological monitoring can provide sufficient radiological and clinical improvement. [ABSTRACT FROM AUTHOR]

Chromosomal 7q34 duplication and BRAF-KIAA1549 fusion is a characteristic genetic alteration in pilocytic astrocytomas. 7q34 gain appears to be common in diffuse astrocytomas, but its significance is unclear. We assessed BRAF gain and BRAF mutations in 123 low-grade diffuse gliomas, including 55 diffuse astrocytomas, 18 oligoastrocytomas and 50 oligodendrogliomas. Quantitative polymerase chain reaction (PCR) revealed BRAF gain in 17/50 (34%) oligodendrogliomas, a significantly higher frequency than in diffuse astrocytomas (7/55; 13%; P = 0.0112). BRAF gain was common in low-grade diffuse gliomas with 1p/19q loss (39%) and those lacking any of the genetic alterations analyzed (31%), but was rare in those with TP53 mutations (2%). Logistic regression analysis showed a significant positive association between 1p/19q loss and BRAF gain ( P = 0.0032) and a significant negative association between TP53 mutations and BRAF gain ( P = 0.0042). Fluorescence in situ hybridization (FISH) analysis of 26 low-grade diffuse gliomas with BRAF gain additionally revealed BRAF-KIAA1549 fusion in one oligodendroglioma. Sequencing of cDNA in 17 low-grade diffuse gliomas showed BRAF-KIAA1549 fusion in another oligodendroglioma. A BRAFV600E mutation was also detected in one oligodendroglioma, and a BRAFA598V in one diffuse astrocytoma. These results suggest that low-grade diffuse gliomas with 1p/19q loss have frequent BRAF gains, and a small fraction of oligodendrogliomas may show BRAF-KIAA1549 fusion. [ABSTRACT FROM AUTHOR]

We recently reported that the vast majority (>90%) of low-grade diffuse gliomas (diffuse astrocytoma, oligoastrocytoma and oligodendroglioma) carry at least one of the following genetic alterations: IDH1/2 mutation, TP53 mutation or 1p/19q loss. Only 7% of cases were triple-negative (ie, lacking any of these alterations). In the present study, array comparative genomic hybridization (CGH) in 15 triple-negative WHO grade II gliomas (eight diffuse astrocytomas and seven oligodendrogliomas) showed loss at 9p21 ( p14ARF, p15INK4b, p16INK4a loci) and 13q14-13q32 (containing the RB1 locus) in three and two cases, respectively. Further analyses in 31 triple-negative cases as well as a total of 160 non-triple-negative cases revealed that alterations in the RB1 pathway (homozygous deletion and promoter methylation of the p15INK4b, p16INK4a and RB1 genes) were significantly more frequent in triple-negative (26%) than in non-triple-negative cases (11%; P = 0.0371). Multivariate analysis after adjustment for age, histology and treatment showed that RB1 pathway alterations were significantly associated with unfavorable outcome for patients with low-grade diffuse glioma [hazard ratio, 3.024 (1.279-6.631); P = 0.0057]. These results suggest that a fraction of low-grade diffuse gliomas lacking common genetic alterations may develop through a distinct genetic pathway, which may include loss of cell-cycle control regulated by the RB1 pathway. [ABSTRACT FROM AUTHOR]