Meningiomas, derived from arachnoid cap cells, are the most common intracranial tumor. High-grade meningiomas, as well as those located at the skull base or near venous sinuses, frequently recur and ...are challenging to manage. Next-generation sequencing is identifying novel pharmacologic targets in meningiomas to complement surgery and radiation. However, due to the lack of in vitro models, the importance and implications of these genetic variants in meningioma pathogenesis and therapy remain unclear. We performed whole exome sequencing to assess single nucleotide variants and somatic copy number variants in four human meningioma cell lines, including two benign lines (HBL-52 and Ben-Men-1) and two malignant lines (IOMM-Lee and CH157-MN). The two malignant cell lines harbored an elevated rate of mutations and copy number alterations compared to the benign lines, consistent with the genetic profiles of high-grade meningiomas. In addition, these cell lines also harbored known meningioma driver mutations in neurofibromin 2 (NF2) and TNF receptor-associated factor 7 (TRAF7). These findings demonstrate the relevance of meningioma cell lines as a model system, especially as tools to investigate the signaling pathways of, and subsequent resistance to, therapeutics currently in clinical trials.
The clinical management of meningioma is guided by tumor grade and biological behavior. Currently, the assessment of tumor grade follows surgical resection and histopathologic review. Reliable ...techniques for pre-operative determination of tumor grade may enhance clinical decision-making.
A total of 175 meningioma patients (103 low-grade and 72 high-grade) with pre-operative contrast-enhanced T1-MRI were included. Fifteen radiomic (quantitative) and 10 semantic (qualitative) features were applied to quantify the imaging phenotype. Area under the curve (AUC) and odd ratios (OR) were computed with multiple-hypothesis correction. Random-forest classifiers were developed and validated on an independent dataset (n = 44).
Twelve radiographic features (eight radiomic and four semantic) were significantly associated with meningioma grade. High-grade tumors exhibited necrosis/hemorrhage (ORsem = 6.6, AUCrad = 0.62-0.68), intratumoral heterogeneity (ORsem = 7.9, AUCrad = 0.65), non-spherical shape (AUCrad = 0.61), and larger volumes (AUCrad = 0.69) compared to low-grade tumors. Radiomic and sematic classifiers could significantly predict meningioma grade (AUCsem = 0.76 and AUCrad = 0.78). Furthermore, combining them increased the classification power (AUCradio = 0.86). Clinical variables alone did not effectively predict tumor grade (AUCclin = 0.65) or show complementary value with imaging data (AUCcomb = 0.84).
We found a strong association between imaging features of meningioma and histopathologic grade, with ready application to clinical management. Combining qualitative and quantitative radiographic features significantly improved classification power.
Judgement, as one of the core tenets of medicine, relies upon the integration of multilayered data with nuanced decision making. Cancer offers a unique context for medical decisions given not only ...its variegated forms with evolution of disease but also the need to take into account the individual condition of patients, their ability to receive treatment, and their responses to treatment. Challenges remain in the accurate detection, characterization, and monitoring of cancers despite improved technologies. Radiographic assessment of disease most commonly relies upon visual evaluations, the interpretations of which may be augmented by advanced computational analyses. In particular, artificial intelligence (AI) promises to make great strides in the qualitative interpretation of cancer imaging by expert clinicians, including volumetric delineation of tumors over time, extrapolation of the tumor genotype and biological course from its radiographic phenotype, prediction of clinical outcome, and assessment of the impact of disease and treatment on adjacent organs. AI may automate processes in the initial interpretation of images and shift the clinical workflow of radiographic detection, management decisions on whether or not to administer an intervention, and subsequent observation to a yet to be envisioned paradigm. Here, the authors review the current state of AI as applied to medical imaging of cancer and describe advances in 4 tumor types (lung, brain, breast, and prostate) to illustrate how common clinical problems are being addressed. Although most studies evaluating AI applications in oncology to date have not been vigorously validated for reproducibility and generalizability, the results do highlight increasingly concerted efforts in pushing AI technology to clinical use and to impact future directions in cancer care.
To provide guidance to clinicians regarding therapy for patients with brain metastases from solid tumors.
ASCO convened an Expert Panel and conducted a systematic review of the literature.
Thirty-two ...randomized trials published in 2008 or later met eligibility criteria and form the primary evidentiary base.
Surgery is a reasonable option for patients with brain metastases. Patients with large tumors with mass effect are more likely to benefit than those with multiple brain metastases and/or uncontrolled systemic disease. Patients with symptomatic brain metastases should receive local therapy regardless of the systemic therapy used. For patients with asymptomatic brain metastases, local therapy should not be deferred unless deferral is specifically recommended in this guideline. The decision to defer local therapy should be based on a multidisciplinary discussion of the potential benefits and harms that the patient may experience. Several regimens were recommended for non-small-cell lung cancer, breast cancer, and melanoma. For patients with asymptomatic brain metastases and no systemic therapy options, stereotactic radiosurgery (SRS) alone should be offered to patients with one to four unresected brain metastases, excluding small-cell lung carcinoma. SRS alone to the surgical cavity should be offered to patients with one to two resected brain metastases. SRS, whole brain radiation therapy, or their combination are reasonable options for other patients. Memantine and hippocampal avoidance should be offered to patients who receive whole brain radiation therapy and have no hippocampal lesions and 4 months or more expected survival. Patients with asymptomatic brain metastases with either Karnofsky Performance Status ≤ 50 or Karnofsky Performance Status < 70 with no systemic therapy options do not derive benefit from radiation therapy.Additional information is available at www.asco.org/neurooncology-guidelines.
Background
H3G34‐mutant diffuse hemispheric glioma (DHG) is recognized as a new, distinct entity in the latest World Health Organization classification for central nervous system tumors and is ...associated with a particularly aggressive course. The authors performed a systematic review and pooled analysis to investigate the frequency of genetic events in these tumors and to determine whether these events were associated with survival trends.
Methods
Two electronic databases were accessed to search for relevant data. Included criteria were studies that had individual patient data on H3.3 G34‐mutant gliomas. To analyze the impact of genetic events on overall survival, Kaplan‐Meier analysis and Cox regression models were used, and corresponding hazard ratios and 95% confidence intervals were computed.
Results
In total, 20 studies with 257 H3G34‐mutant DHGs were included for integrated analyses. The H3 glycine‐to‐valine (H3G34V) mutation showed a significantly worse prognosis than the glycine‐to‐arginine (H3G34R) mutation (median overall survival, 9.9 vs 14.8 months; hazard ratio, 3.040; 95% confidence interval, 1.208‐7.651; P = .018), and this result remained statistically significant in the multivariate Cox regression model. Among H3G34 DHGs, TP53 mutation was the most common genetic alteration (94.9%), followed by ATRX alterations (87.5%), MGMT methylation (79.5%), and PDGFRA alterations (33.2%). The presence of PDGFRA amplification or EGFR amplification conferred poor survival. After adjusting for age and sex, these alterations were still independent indicators for adverse outcomes.
Conclusions
The authors highlight the important role of molecular stratification of H3G34 DHGs, which may help refine our understanding of the natural history of this group of malignant tumors.
The codon 34 glycine‐to‐valine (G34V) mutation in genes encoding the H3 protein is associated with worse overall survival compared with the glycine‐to‐arginine (G34R) mutation. The presence of PDGFRA amplification or EGFR amplification confers poor survival in patients who have H3G34‐mutant diffuse hemispheric gliomas.
Abstract
A recent meeting was held on March 22, 2019, among the FDA, clinical scientists, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocacy groups to ...discuss challenges and potential solutions for increasing development of therapeutics for central nervous system metastases. A key issue identified at this meeting was the need for consistent tumor measurement for reliable tumor response assessment, including the first step of standardized image acquisition with an MRI protocol that could be implemented in multicenter studies aimed at testing new therapeutics. This document builds upon previous consensus recommendations for a standardized brain tumor imaging protocol (BTIP) in high-grade gliomas and defines a protocol for brain metastases (BTIP-BM) that addresses unique challenges associated with assessment of CNS metastases. The “minimum standard” recommended pulse sequences include: (i) parameter matched pre- and post-contrast inversion recovery (IR)–prepared, isotropic 3D T1-weighted gradient echo (IR-GRE); (ii) axial 2D T2-weighted turbo spin echo acquired after injection of gadolinium-based contrast agent and before post-contrast 3D T1-weighted images; (iii) axial 2D or 3D T2-weighted fluid attenuated inversion recovery; (iv) axial 2D, 3-directional diffusion-weighted images; and (v) post-contrast 2D T1-weighted spin echo images for increased lesion conspicuity. Recommended sequence parameters are provided for both 1.5T and 3T MR systems. An “ideal” protocol is also provided, which replaces IR-GRE with 3D TSE T1-weighted imaging pre- and post-gadolinium, and is best performed at 3T, for which dynamic susceptibility contrast perfusion is included. Recommended perfusion parameters are given.
The relentless natural progression of petroclival meningiomas mandates their treatment. The management of these tumors, however, is challenging. Among the issues debated are goals of treatment, ...outcomes, and quality of life, appropriate extent of surgical removal, the role of skull base approaches, and the efficacy of combined decompressive surgery and radiosurgery. The authors report on the outcome in a series of patients treated with the goal of total removal.
The authors conducted a retrospective analysis of 64 cases of petroclival meningiomas operated on by the senior author (O.A.) from 1988 to 2012, strictly defined as those originating medial to the fifth cranial nerve on the upper two-thirds of the clivus. The patients' average age was 49 years; the average tumor size (maximum diameter) was 35.48 ± 10.09 mm (with 59 tumors > 20 mm), and cavernous sinus extension was present in 39 patients. The mean duration of follow-up was 71.57 months (range 4-276 months).
In 42 patients, the operative reports allowed the grading of resection. Grade I resection (tumor, dura, and bone) was achieved in 17 patients (40.4%); there was no recurrence in this group (p = 0.0045). Grade II (tumor, dura) was achieved in 15 patients (36%). There was a statistically significant difference in the rate of recurrence with respect to resection grade (Grades I and II vs other grades, p = 0.0052). In all patients, tumor removal was classified based on postoperative contrast-enhanced MRI, and gross-total resection (GTR) was considered to be achieved if there was no enhancement present; on this basis, GTR was achieved in 41 (64%) of 64 patients, with a significantly lower recurrence rate in these patients than in the group with residual enhancement (p = 0.00348). One patient died from pulmonary embolism after discharge. The mean Karnofsky Performance Status (KPS) score was 85.31 preoperatively (median 90) and improved on follow-up to 88, with 30 patients (47%) having an improved KPS score on follow-up. Three patients suffered a permanent deficit that significantly affected their KPS. Cerebrospinal fluid leak occurred in 8 patients (12.5%), with 2 of them requiring exploration. Eighty-nine percent of the patients had cranial nerve deficits on presentation; of the 54 patients with more than 2 months of follow-up, 21 (32.8%) had persisting cranial nerve deficits. The overall odds of permanent cranial nerve deficit of treated petroclival meningioma was 6.2%. There was no difference with respect to immediate postoperative cranial nerve deficit in patients who had GTR compared with those who had subtotal resection.
Total removal (Grade I or II resection) of petroclival meningiomas is achievable in 76.4% of cases and is facilitated by the use of skull base approaches, with good outcome and functional status. In cases in which circumstances prevent total removal, residual tumors can be followed until progression is evident, at which point further intervention can be planned.
PRAME (PReferentially expressed Antigen in MElanoma) is a biomarker studied in various human cancers. Little is known about the biological implications of PRAME in glioma. We aimed to perform a ...comprehensive analysis to explore PRAME gene expression and its biological and clinicopathological significance in gliomas. We accessed the human cancer atlas (TCGA) database to collect glioma patients (n = 668) with primary tumors and gene expression data. Single nucleotide variants, copy number variation, DNA methylation data, and other clinicopathological factors were also extracted for the analysis. Overall, 170, 484, and 14 tumors showed no expression, low expression (FPKMless than or equal to1), and overexpression (FPKM>1) of the PRAME gene, respectively. The principal component analysis and pathway analyses showed that PRAME-positive gliomas (n = 498), which consisted of tumors with PRAME low expression and overexpression, expressed different oncogenic profiles, possessing higher activity of Hedgehog, P3IK-AKT-mTOR, and Wnt/beta-catenin pathways (p<0.001). DNA methylation analysis also illustrated that PRAME-positive tumors were distributed more densely within a grade 4-related cluster (p<0.001). PRAME positivity was an independent prognostic factor for poor outcomes in a multivariate cox analysis adjusted for clinical characteristics and genetic events. Kaplan-Meier analysis stratified by revised classification showed that PRAME positivity was solely associated with IDH-wildtype glioblastoma, grade 4. Finally, PRAME-overexpressing cases (n = 14) had the worst clinical outcome compared to the PRAME-negative and PRAME-low cohorts (adjusted p<0.001) in pairwise comparisons. PRAME expression statuses may dictate different biological and clinicopathological profiles in IDH-wildtype glioblastoma.
Meningiomas are the most common primary intracranial neoplasms in adults. Current histopathological grading schemes do not consistently predict their natural history. Classic cytogenetic studies have ...disclosed a progressive course of chromosomal aberrations, especially in high-grade meningiomas. Furthermore, the recent application of unbiased next-generation sequencing approaches has implicated several novel genes whose mutations underlie a substantial percentage of meningiomas. These insights may serve to craft a molecular taxonomy for meningiomas and highlight putative therapeutic targets in a new era of rational biology-informed precision medicine.
Abstract
Background
Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate ...selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma.
Methods
DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts.
Results
The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03–0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8–7.2, P < 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22–0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3–11.1, P < 0.001) with clinical implications.
Conclusions
The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone.
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