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Encouraging clinical results using immune checkpoint therapies to target the PD-1 axis in a variety of cancer types have paved the way for new immune therapy trials in brain tumor patients. However, the molecular mechanisms that regulate expression of the PD-1 pathway ligands, PD-L1 and PD-L2, remain poorly understood. To address this, we explored the cell-intrinsic mechanisms of constitutive PD-L1 and PD-L2 expression in brain tumors. PD-L1 and PD-L2 expression was assessed by flow cytometry and qRT-PCR in brain tumor cell lines and patient tumor-derived brain tumor-initiating cells (BTICs). Immunologic effects of PD-L2 overexpression were evaluated by IFN-γ ELISPOT. CD274 and PDCD1LG2 cis-regulatory regions were cloned from genomic DNA and assessed in full or by mutating and/or deleting regulatory elements by luciferase assays. Correlations between clinical responses and PD-L1 and PD-L2 expression status were evaluated in TCGA datasets in LGG and GBM patients. We found that a subset of brain tumor cell lines and BTICs expressed high constitutive levels of PD-L1 and PD-L2 and that PD-L2 overexpression inhibited neoantigen specific T cell IFN-γ production. Characterization of novel cis-regulatory regions in CD274 and PDCD1LG2 lead us to identify that GATA2 is sufficient to drive PD-L1 and PD-L2 expression and is necessary for PD-L2 expression. Importantly, in TCGA datasets, PD-L2 correlated with worse clinical outcomes in glioma patients.. By perturbing GATA2 biology, targeted therapies may be useful to decrease inhibitory effects of PD-L2 in the microenvironment.

Mesenchymal tumors of the central nervous system (CNS) comprise an array of neoplasms that may arise from or secondarily affect the CNS and its immediate surroundings. This review focuses on meningiomas and solitary fibrous tumors, the most common primary CNS mesenchymal tumors, and discusses recent advances in unveiling the molecular landscapes of these neoplasms. An effort is made to underscore those molecular findings most relevant to tumor diagnostics and prognostication from a practical perspective. As molecular techniques become more readily used at the clinical level, such alterations may strengthen formal grading schemes and lend themselves to treatment with targeted therapies., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Exploring the effects of nitrate ions (NO 3 - ) on the bio-oxidation of Fe 2+ and pyrite will help reveal the actual mechanism of acid mine drainage (AMD) production. Long period shaking flask experiments were carried out in order to assess the effect of NO 3 - on the Acidithiobacillus ferrooxidans LX5 (A. ferrooxidans LX5)-mediated bio-oxidation of Fe 2+ and pyrite. In Fe 2+ bio-oxidation systems, A. ferrooxidans LX5 had stronger Fe 2+ oxidation capabilities in a NO 3 - -loaded solution than in a NO 3 - -free solution after 24 days, and the Fe 2+ bio-oxidation capacity of A. ferrooxidans LX5 acclimatized in solutions containing low concentrations (8.2-32.9 mmol/L) of NO 3 - was greater than when it was acclimatized in high NO 3 - concentration solutions (49.4-65.8 mmol/L). In pyrite bio-oxidation systems, in comparison with the system without NO 3 - , pyrite bio-oxidation efficiency was significantly increased when the NO 3 - concentration in the system was 8.2-16.5 mmol/L, and that the pyrite bio-oxidation efficiency in the system containing 8.2 mmol/L of NO 3 - was greater than that for the system with 16.5 mmol/L of NO 3 - . The pyrite bio-oxidation efficiency was inhibited when the NO 3 - concentration was above 32.9 mmol/L. The results from this study can be used to reveal the actual control behavior of NO 3 - on AMD production.

A high tumour mutational burden (hypermutation) is observed in some gliomas 1-5 ; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.

Background: Chronic subdural hematoma (cSDH) is a common neurosurgical condition, with symptoms ranging from headaches to coma. Operative evacuation is the treatment of choice. Subdural reaccumulation leading to reoperation is a vexing postoperative complication., Objective: To present a novel technique for intraoperative aspiration of pneumocephalus via a subdural drain following SDH evacuation as a method of reducing potential subdural space and promoting cerebral expansion, thereby decreasing SDH recurrence., Methods: In this retrospective study, 15 patients who underwent operative evacuation of cSDH between 2008 and 2015 were assessed. Six patients underwent a small craniotomy with intraoperative pneumocephalus aspiration. These patients were matched by age, gender, and anticoagulation status to 9 patients who underwent evacuation of SDH without pneumocephalus aspiration. Quantitative volumetric analysis was performed on the preoperative, postoperative, and 1-mo follow-up computed tomography scan to assess the subdural volume., Results: In the immediate postoperative period, there was no difference in the percentage of residual subdural fluid between the aspiration and control groups (0.291 vs 0.251; P = 1.00). There was a decrease in amount of pneumocephalus present when the aspiration technique was applied (0.182 vs 0.386; P = .041). At 1-mo follow-up, there was a decrease in the residual cSDH volume between the aspiration and the control groups (28.7 mL vs 60.8 mL; P = .011). The long-term evacuation rate was greater in the aspiration group (75.4% vs 51.6%; P = .015)., Conclusion: Intraoperative aspiration of cSDH cavity is a safe technique that may enhance cerebral expansion and reduce likelihood of cSDH recurrence., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Background and Purpose: Previous literature has demonstrated disparity in the postoperative recovery of first and second language function of bilingual neurosurgical patients. However, it is unclear to whether preoperative brain mapping of both languages is needed. In this study, we aimed to evaluate the clinical utility of language task functional MRI (fMRI) implemented in both languages in bilingual patients., Methods: We retrospectively examined fMRI data of 13 bilingual brain tumor patients (age: 23 to 59 years) who performed antonym generation task-based fMRIs in English and non-English language. The usefulness of bilingual language mapping was evaluated using a structured survey administered to 5 neurosurgeons. Additionally, quantitative comparison between the brain activation maps of both languages was performed., Results: Survey responses revealed differences in raters' surgical approach, including asleep versus awake surgery and extent of resection, after viewing the language fMRI maps. Additional non-English fMRI led to changes in surgical decision-making and bettered localization of language areas. Quantitative analysis revealed an increase in laterality index (LI) in non-English fMRI compared to English fMRI. The Dice coefficient demonstrated fair overlap (.458 ± .160) between the activation maps., Conclusion: Bilingual fMRI mapping of bilingual patients allows to better appreciate functionally active language areas that may be neglected in single language mapping. Utility of bilingual mapping was supported by changes in both surgical approach and LI measurements, suggesting its benefit on preoperative language mapping., (© 2020 by the American Society of Neuroimaging.)

Purpose: To evaluate surgical resection with brachytherapy placement as a salvage treatment in patients with recurrent high-grade meningioma who exhausted prior external beam treatment options., Methods: Single-center retrospective review of our institutional experience of brachytherapy implantation from 2012 to 2018. The primary outcome of the study was progression free survival (PFS). Secondary outcomes included overall survival (OS) and complications. A matched cohort of patients not treated with brachytherapy over the same time period was evaluated as a control group. All patients had received prior radiation treatment and underwent planned gross total resection (GTR) surgery., Results: A total of 27 cases were evaluated. Compared with prior treatment, brachytherapy implantation demonstrated a statistically significant improvement in tumor control [HR 0.316 (0.101 - 0.991), p = 0.034]. PFS-6 and PFS-12 were 92.3% and 84.6%, respectively. Compared with the matched control cohort, brachytherapy treatment demonstrated improved PFS [HR 0.310 (0.103 - 0.933), p = 0.030]. Overall survival was not statistically significantly different between groups [HR 0.381 (0.073 - 1.982), p = 0.227]. Overall postoperative complications were comparable between groups, although there was a higher incidence of radiation necrosis in the brachytherapy cohort., Conclusion: Brachytherapy with planned GTR improved PFS in recurrent high-grade meningioma patients who exhausted prior external beam radiation treatment options. Future improvement of brachytherapy dose delivery methods and techniques may continue to prolong control rates and improve outcomes for this challenging group of patients.

Background: Histopathological grading of meningiomas is insufficient for optimal risk stratification. The purpose of the present study was to determine the prognostic value of atypical histopathological features across all nonmalignant meningiomas (World Health Organization [WHO] grade I-II)., Methods: The data from 334 patients with WHO grade I (n = 275) and grade II (n = 59) meningiomas who had undergone surgical resection from 2001 to 2015 at 2 academic centers were pooled. Progression/recurrence (P/R) was determined radiographically and measured from the date of surgery., Results: The median follow-up was 52 months. The patients were stratified by the number of atypical features: 0 (n = 151), 1 (n = 71), 2 (n = 66), 3 (n = 22), and 4 or 5 (n = 24). The risk of P/R increased with an increasing number of atypical features (log-rank test, P = 0.001). The 5-year actuarial rates of P/R stratified by the number of atypical features were as follows: 0, 16.3% (95% confidence interval [CI], 10.7-24.4); 1, 21.7% (95% CI, 12.8-35.2); 2, 28.2% (95% CI, 18.4-41.7); 3, 30.4% (95% CI, 13.8-58.7); and 4 or 5, 51.4% (95% CI, 31.7-74.5). On univariate analysis, the presence of high nuclear/cytoplasmic ratio (P = 0.007), prominent nucleoli (P = 0.007), and necrosis (P < 0.00005) were associated with an increased risk of P/R. On multivariate analysis, the number of atypical features (hazard ratio [HR], 1.30; 95% CI, 1.03-1.63; P = 0.03), ≥4 mitoses per high-power fields (HR, 2.45; 95% CI, 1.17-5.15; P = 0.02), subtotal resection (HR, 3.9; 95% CI, 2.5-6.3; P < 0.0005), and the lack of adjuvant radiotherapy (HR, 2.40; 95% CI, 1.19-4.80; P = 0.01) were associated with an increased risk of P/R., Conclusions: An increased number of atypical features, ≥4 mitoses per 10 high-power fields, subtotal resection, and the lack of adjuvant radiotherapy were independently associated with P/R of WHO grade I-II meningiomas. Patients with these features might benefit from intensified therapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Longitudinal measurement of glioma burden with MRI is the basis for treatment response assessment. In this study, we developed a deep learning algorithm that automatically segments abnormal fluid attenuated inversion recovery (FLAIR) hyperintensity and contrast-enhancing tumor, quantitating tumor volumes as well as the product of maximum bidimensional diameters according to the Response Assessment in Neuro-Oncology (RANO) criteria (AutoRANO)., Methods: Two cohorts of patients were used for this study. One consisted of 843 preoperative MRIs from 843 patients with low- or high-grade gliomas from 4 institutions and the second consisted of 713 longitudinal postoperative MRI visits from 54 patients with newly diagnosed glioblastomas (each with 2 pretreatment "baseline" MRIs) from 1 institution., Results: The automatically generated FLAIR hyperintensity volume, contrast-enhancing tumor volume, and AutoRANO were highly repeatable for the double-baseline visits, with an intraclass correlation coefficient (ICC) of 0.986, 0.991, and 0.977, respectively, on the cohort of postoperative GBM patients. Furthermore, there was high agreement between manually and automatically measured tumor volumes, with ICC values of 0.915, 0.924, and 0.965 for preoperative FLAIR hyperintensity, postoperative FLAIR hyperintensity, and postoperative contrast-enhancing tumor volumes, respectively. Lastly, the ICCs for comparing manually and automatically derived longitudinal changes in tumor burden were 0.917, 0.966, and 0.850 for FLAIR hyperintensity volume, contrast-enhancing tumor volume, and RANO measures, respectively., Conclusions: Our automated algorithm demonstrates potential utility for evaluating tumor burden in complex posttreatment settings, although further validation in multicenter clinical trials will be needed prior to widespread implementation., (The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Lilium is one of the most popular flower crops worldwide, and some species are also used as vegetables and medicines. The availability of and easy access to diverse Lilium genetic resources are essential for plant genetic improvements. Cryopreservation is currently considered as an ideal means for the long-term preservation of plant germplasm. Over the last two decades, great efforts have been exerted in studies of Lilium cryopreservation and progress has been made in the successful cryopreservation of pollen, seeds and shoot tips in Lilium . Genes that exist in Lilium, including those that regulate flower shape, color and size, and that are resistant to cold stress and diseases caused by fungi and viruses, provide a rich source of valuable genetic resources for breeding programs to create novel cultivars required by the global floriculture and ornamental markets. Successful cryopreservation of Lilium spp. is a way to preserve these valuable genes. The present study provides updated and comprehensive information about the development of techniques that have advanced Lilium cryopreservation. Further ideas are proposed to better direct future studies on Lilium cryobiotechnology., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2019.)

Background: Described variations of tentorial venous anatomy impact surgical sectioning of the tentorium in skull base approaches; however, described configurations do not consistently explain postoperative complications. To understand the outcomes of 2 clinical cases we studied the tentorial venous anatomy of 2 cadavers., Methods: The venous anatomy of the tentorium isolated in 2 uninjected fresh cadaver head specimens with preserved bridging veins was observed by transillumination before and after methylene blue injection of the dural sinuses and tentorial veins. Our findings in cadavers were applied to explain the clinical and radiologic (magnetic resonance imaging and computed tomographic venography) findings in the 2 cases presented., Results: A consistent transtentorial venous system, arising from transverse and straight sinuses, communicating with supra- and infratentorial bridging veins was seen in the cadaver and patient radiography (magnetic resonance imaging and computed tomographic venography). Our first patient had a cerebellar venous infarct from compromise of the venous drainage from the adjacent brain after ligation of a temporal lobe bridging vein to the tentorium. Our second patient suffered no clinical effects from bilateral transverse sinus occlusion due to drainage through the accessory venous system within the tentorium., Conclusions: Herein, we elaborate on transtentorial venous anatomy. These veins, previously reported to obliterate in completed development of the tentorium, remain patent with consistent observed configuration. The same transtentorial venous system was observed in both cases and provided insight to their outcomes. These findings emphasize the importance of the transtentorial venous system physiologically and in surgical approaches., (Published by Elsevier Inc.)

Objective: Few studies describe long-term functional outcomes of pediatric patients who have undergone lumbar microdiscectomy (LMD) because of the rarity of pediatric disc herniation and the short follow-up periods. The authors analyzed risk factors, clinical presentation, complications, and functional outcomes of a single-institution series of LMD patients over a 19-year period., Methods: A retrospective case series was conducted of pediatric LMD patients at a large pediatric academic hospital from 1998 to 2017. The authors examined premorbid risk factors, clinical presentation, physical examination findings, type and duration of conservative management, indications for surgical intervention, complications, and postoperative outcomes., Results: Over the 19-year study period, 199 patients underwent LMD at the authors' institution. The mean age at presentation was 16.0 years (range 12-18 years), and 55.8% were female. Of these patients, 70.9% participated in competitive sports, and among those who did not play sports, 65.0% had a body mass index greater than 25 kg/m2. Prior to surgery, conservative management had failed in 98.0% of the patients. Only 3 patients (1.5%) presented with cauda equina syndrome requiring emergent microdiscectomy. Complications included 4 cases of postoperative CSF leak (2.0%), 1 case of a noted intraoperative CSF leak, and 3 cases of wound infection (1.5%). At the first postoperative follow-up appointment, minimal or no pain was reported by 93.3% of patients. The mean time to return to sports was 9.8 weeks. During a mean follow-up duration of 8.2 years, 72.9% of patients did not present again after routine postoperative appointments. The total risk of reoperation was a rate of 7.5% (3.5% of patients underwent reoperation for the same level; 4.5% underwent adjacent-level decompression, and one patient [0.5%] ultimately underwent a fusion)., Conclusions: Microdiscectomy is a safe and effective treatment for long-term relief of pain and return to daily activities among pediatric patients with symptomatic lumbar disc disease in whom conservative management has failed.

Background: Perioperative cerebral infarction is a potential complication of glioma resection, of which insular tumors are at higher risk because of the proximity of middle cerebral artery branches, including the lateral lenticulostriates and long insular arteries. In this study, 3 patients received three-dimensional rotational angiography, which was fused with magnetic resonance imaging (MRI) for frameless stereotactic navigation during dominant-hemisphere insular glioma resection., Methods: All patients obtained a preoperative catheter angiogram with a three-dimensional rotational acquisition of the ipsilateral internal carotid artery. The pixel-based axial three-dimensional angiography data, thin-cut structural MRI, tractography from diffusion tensor imaging, and expressive language activation from functional MRI were uploaded into the iPlan software (Brainlab, Heimstetten, Germany) and fused. The target tumor, regional blood vessels, adjacent functional areas, and their associated fiber tracts were segmented and overlaid on the appropriate MRI sequence. This image fusion was used preoperatively to visualize the relationship of the mass with the adjacent vasculature and intraoperatively for frameless stereotactic navigation to optimize preservation of arterial structures., Results: Three patients aged 27-60 years with excellent baseline functional status presented with seizures and were found to have a large dominant-hemisphere T2 hyperintense nonenhancing insular mass. Surgical resection was performed using multimodality neuronavigation. None sustained a postoperative arterial infarction or a perioperative neurologic deficit., Conclusions: Neuronavigation using a fusion of three-dimensional rotational angiography with MRI is a technique that can be used for preoperative planning and during resection of insular gliomas to optimize preservation of adjacent arteries., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The vast majority of pituitary tumors are benign and behave accordingly; however, a fraction are invasive and are more aggressive, with a very small fraction being frankly malignant. The cellular pathways that drive transformation in pituitary neoplasms are poorly characterized, and current classification methods are not reliable correlates of clinical behavior. Novel techniques in epigenetics, the study of alterations in gene expression without changes to the genetic code, provide a new dimension to characterize tumors, and may hold implications for prognostication and management. Methods: We conducted a review of primary epigenetic studies of pituitary tumors with a focus on histone modification, DNA methylation, and transcript modification. Results: High levels of methylation have been identified in invasive and large pituitary tumors. DNA methyltransferase overexpression has been detected in pituitary tumors, especially in macroadenomas. Methylation differences at CpG sites in promoter regions may distinguish several types of tumors from normal pituitary tissue. Histone modifications have been linked to increased p53 expression and longer progression-free survival in pituitary tumors; sirtuins are expressed at higher values in GH-expressing compared to nonfunctional adenomas and correlate inversely with size in somatotrophs. Upregulation in citrullinating enzymes may be an early pathogenic marker of prolactinomas. Numerous genes involved with cell growth and signaling show altered methylation status for pituitary tumors, including cell cycle regulators, components of signal transduction pathways, apoptotic regulators, and pituitary developmental signals. Conclusions: The limited clinical predictive capacity of the current pituitary tumor classification system suggests that tumor subclasses likely remain to be discovered. Ongoing epigenetic studies could provide a basis for adding methylation and/or acetylation screening to standard pituitary tumor workups. Identifying robust correlations between tumor epigenetics and corresponding histological, radiographic, and clinical course information could ultimately inform clinical decision-making.

Importance: Neurosurgical resection represents an important management strategy for patients with large, symptomatic brain metastases and increasingly is followed by stereotactic radiation as opposed to whole-brain radiation. Whether neurosurgical resection is associated with tumor spread beyond the resection site and adjuvant stereotactic radiation field remains unknown., Objective: To characterize the association and incidence of pachymeningeal seeding with neurosurgical resection in patients with brain metastases treated with adjuvant stereotactic radiation., Design, Setting, and Participants: Retrospective cohort study of a consecutive sample of patients with newly diagnosed brain metastases managed with neurosurgical resection and stereotactic radiation (n = 318) vs radiation alone (n = 870) between 2001 and 2015., Main Outcomes and Measures: Incidence of pachymeningeal seeding (dural and/or outer arachnoid) and leptomeningeal disease in patients treated with neurosurgical resection and stereotactic radiation vs radiation alone and the risk factors and outcomes associated with pachymeningeal seeding in patients treated with neurosurgical resection followed by stereotactic radiation., Results: In 1188 patients with newly diagnosed brain metastases, 133 men and 185 women (mean [SD] age, 58.9 [11.5] years) underwent neurosurgical resection. Resection was found to be associated with pachymeningeal seeding (36 of 318 patients vs 0 of 870 patients; P < .001) but not leptomeningeal disease (hazard ratio [HR], 1.14; 95% CI, 0.73-1.77; P = .56). In total, 36 (8.4%) of 428 operations were complicated by pachymeningeal seeding, with a higher incidence noted with resection of previously irradiated vs unirradiated metastases (HR, 2.39; 95% CI, 1.25-4.57; P = .008). Patients with pachymeningeal seeding had relatively low rates of subsequent development of new brain metastases and leptomeningeal disease (8 [16%] of 51 and 6 [13%] of 48, respectively). Among patients with pachymeningeal seeding, neurologic death primarily owing to progressive pachymeningeal disease accounted for 26 (72%) of 36 deaths, but when treated with salvage radiation, 49.1% of patients survived 1 year or longer., Conclusions and Relevance: In the era of omission of adjuvant whole-brain radiation after neurosurgical resection, pachymeningeal seeding beyond the stereotactic radiation field represents a notable oncologic event that often proves difficult to salvage. However, in some patients, disease control can be achieved with radiotherapeutic approaches.

Background: Pneumoperitoneum after surgical manipulation of the abdomen implies a perforation. Rare cases of nonoperated cancer patients, largely with gastrointestinal or genitourinary cancers, have been noted to have radiologic findings of pneumatosis intestinalis and/or pneumoperitoneum as a complication of molecular-targeted therapy (MTT) without confounding factors for perforation. We present a patient with a cranial malignancy treated with bevacizumab who subsequently manifested with pneumatosis intestinalis., Case Description: A 67-year-old man with metastatic melanoma, non-small cell lung cancer, and recurrent cerebellar subependymoma was initiated on bevacizumab treatment for subependymoma recurrence. He subsequently underwent an uncomplicated ventriculoperitoneal shunt for progressive obstructive hydrocephalus, confirmed by a normal postoperative abdominal radiograph. One week later, he returned with worsening lethargy and a computed tomography consistent with pneumomediastinum and pneumoperitoneum. Due to concern for bowel perforation, the patient underwent diagnostic laparoscopy and removal of ventriculoperitoneal shunt. Focal sigmoid pneumatosis was identified without any signs of bowel perforation or ischemia. Bevacizumab was discontinued, and the patient's radiologic and clinical findings improved., Conclusions: With increasing utilization of MTTs in brain tumor management, we raise MTT as a potential cause for pneumoperitoneum in neurosurgical patients. Pneumoperitoneum after extracranial procedures still requires workup and management for potential bowel perforation, but alternative causes such as bevacizumab should also be considered. Pneumatosis intestinalis patients on MTT can have benign physical examinations and will resolve, in the majority of cases, on discontinuation of the drug., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: Isocitrate dehydrogenase (IDH) and 1p19q codeletion status are importantin providing prognostic information as well as prediction of treatment response in gliomas. Accurate determination of the IDH mutation status and 1p19q co-deletion prior to surgery may complement invasive tissue sampling and guide treatment decisions., Methods: Preoperative MRIs of 538 glioma patients from three institutions were used as a training cohort. Histogram, shape, and texture features were extracted from preoperative MRIs of T1 contrast enhanced and T2-FLAIR sequences. The extracted features were then integrated with age using a random forest algorithm to generate a model predictive of IDH mutation status and 1p19q codeletion. The model was then validated using MRIs from glioma patients in the Cancer Imaging Archive., Results: Our model predictive of IDH achieved an area under the receiver operating characteristic curve (AUC) of 0.921 in the training cohort and 0.919 in the validation cohort. Age offered the highest predictive value, followed by shape features. Based on the top 15 features, the AUC was 0.917 and 0.916 for the training and validation cohort, respectively. The overall accuracy for 3 group prediction (IDH-wild type, IDH-mutant and 1p19q co-deletion, IDH-mutant and 1p19q non-codeletion) was 78.2% (155 correctly predicted out of 198)., Conclusion: Using machine-learning algorithms, high accuracy was achieved in the prediction of IDH genotype in gliomas and moderate accuracy in a three-group prediction including IDH genotype and 1p19q codeletion.

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., (© 2019 American Cancer Society.)

Background: Meningiomas are the most common primary brain tumors in adults. Due to their variable growth rates and irregular tumor shapes, response assessment in clinical trials remains challenging and no standard criteria have been defined. We evaluated 1D, 2D, and volume imaging criteria to assess whether a volumetric approach might be a superior surrogate for overall survival (OS)., Methods: In this retrospective multicenter study, we evaluated the clinical and imaging data of 93 patients with recurrent meningiomas treated with pharmacotherapy. One-dimensional (1D), 2D, and volumetric measurements of enhancing tumor on pre- and post-treatment MRI were compared at 6 and 12 months after treatment initiation. Cox proportional hazards models were used to examine the relationship between each imaging criterion and OS., Results: The median age of the patient cohort is 51 years (range 12-88), with 14 World Health Organization (WHO) grade I, 53 WHO grade II, and 26 WHO grade III meningiomas. Volumetric increase of 40% and unidimensional increase by 10 mm at 6 months and 12 months provided the strongest association with overall survival (HR = 2.58 and 3.24 respectively, p<0.01). Setting a volume change threshold above 40% did not correlate with survival. The interobserver agreement of 1D, 2D, and volume criteria is only moderate (kappa = 0.49, 0.46, 0.52, respectively). None of the criteria based on tumor size reduction were associated with OS (P > 0.09)., Conclusion: Compared with 1D (Response Evaluation Criteria In Solid Tumors 1.1) and 2D (Response Assessment in Neuro-Oncology) approaches, volumetric criteria for tumor progression has a stronger association with OS, although the differences were only modest. The interobserver variability is moderate for all 3 methods. Further validation of these findings in an independent patient cohort is needed., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction  Nationwide databases are frequently used resources for assessing practice patterns and clinical outcomes. However, analyses based on billing codes may be limited by the inconsistent application of current procedural terminology (CPT) codes to specific operations. We investigated the variability among commonly used CPT codes for vestibular schwannomas resection and sought to identify factors that underlie this variation. Methods  The surgical procedure for 274 cases of vestibular schwannoma resections from two institutions was reviewed and classified as retrosigmoid, translabyrinthine, or middle fossa approaches. We then assessed the CPT codes assigned to each case and analyzed their association with surgical approach, surgeons involved, the coding specialty, and year of surgery. We further compared the incidence of CPT codes assigned for vestibular schwannoma surgeries in the American College Surgeons National Surgical Quality Improvement Program (NSQIP) database from 2010 to 2014. Results  The majority (65%) of vestibular schwannoma resections within the institutional cohort were billed with skull base approach and/or excision codes, whereas 76% of cases in NSQIP were associated with a single craniotomy for tumor code. The use of skull base codes over the past decade increased within our institutional cohort but remained relatively stable within NSQIP. CPT codes did not consistently reflect the operative approaches for vestibular schwannomas. Conclusion  We observed significant variability in coding patterns for vestibular schwannoma surgeries within institutions, surgical practices, and national databases. These results call for discretion in interpretation of data from aggregated billing code-based nationwide databases and suggests a role for institutional standardization of CPT assignments for the same approaches.

Background: Brain metastases commonly manifest in patients with cancer, with ∼20%-50% presenting with 1 intracranial lesion. Among patients with 1, small brain metastasis and controlled or absent extracranial disease, it remains unclear whether aggressive intracranial management using neurosurgical resection plus cavity stereotactic radiosurgery/stereotactic radiotherapy (SRS/SRT) rather than SRS/SRT alone is beneficial. In patients with controlled or absent extracranial disease and 1 brain metastasis ≤2 cm in size, we evaluated the effect of surgery plus SRS/SRT compared with SRS/SRT on oncologic outcomes, including overall survival., Methods: We retrospectively identified 86 patients with controlled or absent extracranial disease and 1 brain metastasis ≤2 cm in size who had been treated from 2000 to 2015 at our institution. We examined differences in the rates of local and distant failure, use of salvage treatment, and other oncologic outcomes, including all-cause mortality., Results: The baseline characteristics were similar between the 2 cohorts. The median follow-up period for the surviving patients was 38 months. On multivariable analysis, surgical resection plus cavity SRS/SRT was associated with a lower risk of all-cause mortality (hazard ratio, 0.44; 95% confidence interval, 0.19-1.00; P = 0.05) compared with SRS/SRT alone. The 1- and 2-year rates of overall survival were 100% and 88% versus 74% and 52% for surgery plus cavity SRS/SRT versus SRS/SRT alone, respectively., Conclusions: Aggressive, local therapy, including neurosurgical resection, might benefit patients with 1 brain metastasis in the context of controlled or absent systemic disease, even if the lesion in question is small. Further studies are needed to evaluate these associations., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The archetypal imaging characteristics of meningiomas are among the most stereotypic of all central nervous system (CNS) tumors. In the era of plain film and ventriculography, imaging was only performed if a mass was suspected, and their results were more suggestive than definitive. Following more than a century of technological development, we can now rely on imaging to non-invasively diagnose meningioma with great confidence and precisely delineate the locations of these tumors relative to their surrounding structures to inform treatment planning. Asymptomatic meningiomas may be identified and their growth monitored over time; moreover, imaging routinely serves as an essential tool to survey tumor burden at various stages during the course of treatment, thereby providing guidance on their effectiveness or the need for further intervention. Modern radiological techniques are expanding the power of imaging from tumor detection and monitoring to include extraction of biologic information from advanced analysis of radiological parameters. These contemporary approaches have led to promising attempts to predict tumor grade and, in turn, contribute prognostic data. In this supplement article, we review important current and future aspects of imaging in the diagnosis and management of meningioma, including conventional and advanced imaging techniques using CT, MRI, and nuclear medicine.

Meningiomas are the most common primary intracranial neoplasm. The current World Health Organization (WHO) classification categorizes meningiomas based on histopathological features, but emerging molecular data demonstrate the importance of genomic and epigenomic factors in the clinical behavior of these tumors. Treatment options for symptomatic meningiomas are limited to surgical resection where possible and adjuvant radiation therapy for tumors with concerning histopathological features or recurrent disease. At present, alternative adjuvant treatment options are not available in part due to limited historical biological analysis and clinical trial investigation on meningiomas. With advances in molecular and genomic techniques in the last decade, we have witnessed a surge of interest in understanding the genomic and epigenomic landscape of meningiomas. The field is now at the stage to adopt this molecular knowledge to refine meningioma classification and introduce molecular algorithms that can guide prediction and therapeutics for this tumor type. Animal models that recapitulate meningiomas faithfully are in critical need to test new therapeutics to facilitate rapid-cycle translation to clinical trials. Here we review the most up-to-date knowledge of molecular alterations that provide insight into meningioma behavior and are ready for application to clinical trial investigation, and highlight the landscape of available preclinical models in meningiomas.

The effect of adjuvant radiotherapy in management for high-grade meningiomas, especially atypical meningiomas, remains controversial. We aimed to explore the role of adjuvant radiotherapy in this population. A total of 162 adults with high-grade meningiomas (99 atypical meningiomas and 63 anaplastic meningiomas) were treated from 2003 to 2008 at Huashan Hospital. One hundred and seventeen patients presented with primary and 45 with recurrent disease. One hundred and fifteen patients (70.9%) were treated with adjuvant radiotherapy after surgical resection. The median follow-up was 76.5 months (range 1-142 months). Kaplan-Meier survival curve and Cox proportional hazards modeling were used for analyses. Adjuvant radiotherapy was associated with prolonged progression-free survival (PFS) and overall survival (OS) in patients with newly diagnosed anaplastic meningiomas irrespective of extent of resection (PFS, P = .001; OS, P = .003). Gross total resection was the only independent prognostic factor for those with newly diagnosed atypical meningiomas (PFS, P < .001; OS, P = .012). A survival benefit for adjuvant radiation was also found in subgroup analysis of patients with high-grade meningiomas who underwent subtotal resection (PFS, P = .023; OS, P = .013). Among recurrent high-grade meningiomas, radiotherapy offered no statistically significant improvement in either PFS or OS. Adjuvant radiotherapy is associated with improved survival in patients with newly diagnosed anaplastic meningiomas and those high-grade meningiomas following subtotal resection. However, there was no significant correlation identified between postoperative radiation and outcome for recurrent high-grade meningiomas. Future prospective randomized trials may help clarify the optimal tailored treatment for patients with high-grade meningioma., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: Readmission and reoperation are risks in the resection of benign cranial nerve tumors (BCNTs). This report analyzes the impact of patient-level and surgical factors on these adverse outcomes., Methods: This retrospective cohort review comprised patients with a diagnosis of BCNT enrolled in the American College of Surgeons National Surgical Quality Improvement Program registry from 2011 to 2015. Multivariate logistic regression was used to determine the impact of select medical and operative factors on the primary outcomes of readmission and reoperation within 30 days, adjusted for relevant covariates., Results: We identified 996 patients who underwent resection of a BCNT. The most frequent major complications were readmission (11%), reoperation (8%), surgical site infections (2.6%), and venous thromboembolism (1.5%). The most frequent indications for readmission were management of infection (2.5%), cerebrospinal fluid leak (2.3%), and hydrocephalus (0.5%). Repair of cranial and meningeal defects (3.0%), correction of lagophthalmos (1.2%), and repair of middle ear defects (1.0%) were the most common indications for reoperation. Logistic regression revealed that extremes of age were associated with readmission, whereas preoperative steroid usage, long operative time, and postoperative length of stay >3 days were associated with reoperation (P < 0.05). Obesity trended toward an association with readmission and reoperation., Conclusions: Extremes of age were associated with readmission; preoperative steroid use, long operative time, and postoperative length of stay >3 days were associated with reoperation. Surgeons should consider these factors when assessing risk of postoperative complications for BCNTs., (Copyright © 2018 Elsevier Inc. All rights reserved.)

No standard criteria exist for assessing response and progression in clinical trials involving patients with meningioma, and there is no consensus on the optimal endpoints for trials currently under way. As a result, there is substantial variation in the design and response criteria of meningioma trials, making comparison between trials difficult. In addition, future trials should be designed with accepted standardized endpoints. The Response Assessment in Neuro-Oncology Meningioma Working Group is an international effort to develop standardized radiologic criteria for treatment response for meningioma clinical trials. In this proposal, we present the recommendations for response criteria and endpoints for clinical trials involving patients with meningiomas.

Objective: The authors report the diagnosis, management, and outcomes of 6 cases of spindle cell oncocytoma (SCO) in an effort to guide clinical diagnosis and management of these uncommon lesions., Methods: This study is a retrospective review of cases involving adult patients who underwent resection of pituitary lesions at the authors' institutions between January 2000 and October 2017. The authors identified patients with histopathological confirmation of SCO and collected clinical data, including preoperative, perioperative, and postoperative management, complications, and outcomes., Results: Six patients with SCO were identified. Clinical findings at initial presentation included visual disturbances, dizziness, and headache. All patients underwent resection. Four resections were initially performed by the transsphenoidal approach, and 2 resections were performed by craniotomy at an outside institution with subsequent transsphenoidal reoperations. Neither necrosis nor increased mitotic activity was seen in the tumor samples. All samples stained positive for S100 protein and thyroid transcription factor 1 and negative for glial fibrillary acidic protein and pituitary hormones. Five of the samples stained positive for epithelial membrane antigen. The average MIB-1 index was 8.3% (range 2-17). Postoperatively, 3 of the 6 patients received further treatment for progression of residual tumor or for recurrence, 2 have stable residual tumor, and 1 has had no recurrence after gross-total resection. Two patients developed postoperative complications of transient sixth cranial nerve palsy and diplopia. There were no other complications., Conclusions: SCO poses both a diagnostic and therapeutic challenge. These tumors are often initially misdiagnosed as nonfunctional pituitary adenomas because of their sellar location and nonspecific symptomatology. Postoperatively, SCO must also be distinguished from other neoplasms of the posterior pituitary gland through histopathological examination. Resection of SCO can be challenging, given its highly vascular and adherent nature. Long-term follow-up is critical, as the tumor is associated with higher recurrence and progression rates compared to other benign neoplasms of the sella.

Objectives: Updated multi-institutional database studies assessing perioperative risk factors on 30-day morbidity and mortality after skull base surgeries are limited. We aim to identify perioperative risk factors and report the incidence of 30-day morbidity and mortality in adult patients after skull base surgery., Patients and Methods: We queried the 2007-2016 American College of Surgeons National Surgical Quality Improvement program database to identify patients who underwent anterior, middle, or posterior skull base surgery. We performed multivariable logistic regression to identify risk factors associated with 30-day morbidity and mortality. Postoperative events were compared between propensity score matched cohorts (no morbidity versus 30-day morbidity)., Results: The final analysis included 1028 adult (≥18 years old) patients. The incidence of 30-morbidity and mortality was 14.6% and 1.6%, respectively. Postoperative ventilator dependence (52.9%) followed by pneumonia (23.5%) and unplanned intubation (23.5%) had the highest prevalence among those with 30-day mortality. The adjusted odds of 30-day morbidity was significantly higher among patients with functional dependency, American Society of Anesthesiologists Physical Status ≥4, hyponatremia, and anemia (p < 0.05). The adjusted odds of 30-day mortality was significantly increased among patients with sepsis, bleeding disorder, disseminated cancer, and older age (p < 0.05)., Conclusion: Clinical perioperative factors are significantly associated with 30-day morbidity and mortality after skull base surgery. The reported rate of 30-day morbidity and mortality was similar to earlier studies and therefore highlights the need for continued quality improvement., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We explored the clinical and pathological impact of epidermal growth factor receptor (EGFR) extracellular domain missense mutations. Retrospective assessment of 260 de novo glioblastoma patients revealed a significant reduction in overall survival of patients having tumors with EGFR mutations at alanine 289 (EGFR A289D/T/V ). Quantitative multi-parametric magnetic resonance imaging analyses indicated increased tumor invasion for EGFR A289D/T/V mutants, corroborated in mice bearing intracranial tumors expressing EGFR A289V and dependent on ERK-mediated expression of matrix metalloproteinase-1. EGFR A289V tumor growth was attenuated with an antibody against a cryptic epitope, based on in silico simulation. The findings of this study indicate a highly invasive phenotype associated with the EGFR A289V mutation in glioblastoma, postulating EGFR A289V as a molecular marker for responsiveness to therapy with EGFR-targeting antibodies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

OBJECTIVE Craniopharyngiomas are among the most challenging of intracranial tumors to manage because of their pattern of growth, associated morbidities, and high recurrence rate. Complete resection on initial encounter can be curative, but it may be impeded by the risks posed by the involved neurovascular structures. Recurrent craniopharyngiomas, in turn, are frequently refractory to additional surgery and adjuvant radiation or chemotherapy. METHODS The authors conducted a review of primary literature. RESULTS Recent advances in the understanding of craniopharyngioma biology have illuminated potential oncogenic targets for pharmacotherapy. Specifically, distinct molecular profiles define two histological subtypes of craniopharyngioma: adamantinomatous and papillary. The discovery of overactive B-Raf signaling in the adult papillary subtype has led to reports of targeted inhibitors, with a growing acceptance for refractory cases. An expanding knowledge of the biological underpinnings of craniopharyngioma will continue to drive development of targeted therapies and immunotherapies that are personalized to the molecular signature of each individual tumor. CONCLUSIONS The rapid translation of genomic findings to medical therapies for recurrent craniopharyngiomas serves as a roadmap for other challenging neurooncological diseases.

Background: Skull base chordomas in children are extremely rare. Their course, management, and outcome have not been defined., Objective: To describe the preeminent clinical and radiological features in a series of pediatric patients with skull base chordomas and analyze the outcome of a cohort who underwent uniform treatment. We emphasize predictors of overall survival and progression-free survival, which aligns with Collins' law for embryonal tumors., Methods: Thirty-one patients with a mean age of 10.7 yr (range 0.8-22) harboring skull base chordomas were evaluated. We retrospectively analyzed the outcomes and prognostic factors for 18 patients treated by the senior author, with uniform management of surgery with the aim of gross total resection and adjuvant proton-beam radiotherapy. Mean follow-up was 119.2 mo (range 8-263)., Results: Abducens nerve palsy was the most common presenting symptom. Imaging disclosed large tumors that often involve multiple anatomical compartments. Patients undergoing gross total resection had significantly increased progression-free survival (P = .02) and overall survival (P = .05) compared with those having subtotal resection. Those who lived through the period of risk for recurrence without disease progression had a higher probability of living entirely free of progression (P = .03; odds ratio = 16.0). Age, sex, and histopathological variant did not yield statistical significance in survival., Conclusion: Long-term overall and progression-free survival in children harboring skull base chordomas can be achieved with gross surgical resection and proton-beam radiotherapy, despite an advanced stage at presentation. Collins' law does apply to pediatric skull base chordomas, and children with this disease have a high hope for cure.

The epochal developments in the treatment of meningioma-microsurgery, skull base techniques, and radiation therapy-will be appended to include the rational application of targeted and immune therapeutics, previously ill-fitting concepts for a tumor that has traditionally been a regarded as a surgical disease. The genomic and immunological architecture of these tumors continues to be defined in ever-greater detail. Grade I meningiomas are driven by NF2 alterations or mutations in AKT1, SMO, TRAF7, PIK3CA, KLF4, POLR2A, SUFU, and SMARCB1. Higher-grade tumors, however, are driven nearly exclusively by NF2/chr22 loss and are marked by infrequent targetable mutations, although they may harbor a greater mutation burden overall. TERT mutations may be more common in tumors that progress in histological grade; SMARCE1 alteration has become a signature of the clear cell subtype; and BAP1 in rhabdoid variants may confer sensitivity to pharmacological inhibition. Compared with grade I meningiomas, the most prominent alteration in grade II and III meningiomas is a significant increase in chromosomal gains and losses, or copy number alterations, which may have behavioral implications. Furthermore, integrated genomic analyses suggest phenotypic subgrouping by methylation profile and a specific role for PRC2 complex activation. Lastly, there exists a complex phylogenetic relationship among recurrent high-grade tumors, which continues to underscore a role for the most traditional therapy in our arsenal: surgery.

Background: Adult tethered cord syndrome is a rare neurologic disorder that classically presents with back or leg pain, weakness, and urinary dysfunction. Spinal cord tethering has been associated with acquired Chiari malformations. Whereas the effects of tethered cord release on Chiari malformation symptoms have been described previously, we report an unusual case of acquired tethered cord syndrome following Chiari decompression., Case Description: We report a 68-year-old man with a history of distant T12-level spinal cord injury and 2 weeks of progressive bilateral lower extremity weakness. The patient underwent a T12-L1 laminectomy in 1977, complicated by arachnoiditis and syringomyelia, with eventual placement of a syringopleural shunt. He remained neurologically stable until 2012, when he underwent a suboccipital craniectomy for Chiari decompression for new-onset headache and dysphagia. Ten days later, the patient noted progressive leg weakness and radiographic evidence of spinal cord tethering at the T11-T12 level. A T10-L1 laminectomy and medical facetectomy was undertaken for detethering with postoperative recovery of ambulatory function with assistance., Conclusions: Our patient exhibited an unusual acquisition of tethered cord syndrome. The tethering of the spinal cord may have been triggered by arachnoid adhesions from initial lumbar surgery 35 years before presentation and subsequently exacerbated by alterations of cerebrospinal fluid dynamics after Chiari decompression. Given the potentially devastating sequelae of tethered cord syndrome, investigation of cerebrospinal fluid flow dynamics may be beneficial before operative intervention in patients with risk factors for a tethered cord who exhibit adult-onset Chiari malformation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Dynamic CT angiography (dCTA) augments traditional CTA with temporal resolution and has been demonstrated to influence operative planning in skull base surgery., Methods: Three hundred twenty-five dynamic CTA cases from a single institution were reviewed for indication of study, findings, and comparison to other modalities of imaging., Results: The most frequent application of dCTA was pre-operative surgical planning (59.4%); resection of skull base tumors represented the majority of these pre-operative studies (93.3%). It was also used to evaluate new neurological symptoms (20.9%). Of these, the most common symptoms prompting a dCTA study included headache (22.1%) and visual field deficit (11.8%). The most commonly visualized vascular lesions were partial (22.9%) and complete vascular occlusions (9.0%). Dynamic CTA has also been useful in post-operative imaging for vascular malformations (9.5%) and tumors (2.5%). Finally, dCTA was employed to evaluate ambiguous abnormal findings observed on other imaging modalities (7.7%). Cerebral dCTA ruled out inconclusive abnormal vascular findings visualized on other imaging modalities (64.0%) more frequently than it confirmed them (32.0%), and was inconclusive in a singular case (4.0%)., Conclusions: Cerebral dCTA is an evolving new technology with a diverse spectrum of potential applications. In addition to its role in guiding pre-operative planning for skull base surgical cases, dynamic CTA offers excellent spatial and temporal resolution for assessment of vascular lesions.

Surgery is curative for most meningiomas, but a minority of these tumors recur and progress after resection. Initial trials of medical therapies for meningioma utilized nonspecific cytotoxic chemotherapies. The presence of hormone receptors on meningioma ushered in trials of hormone-mimicking agents. While these trials expanded clinical understanding of meningioma, they ultimately had limited efficacy in managing aggressive lesions. Subsequent detection of misregulated proteins and genomic aberrancies motivated the study of therapies targeting specific biological disturbances observed in meningioma. These advances led to trials of targeted kinase inhibitors and immunotherapies, as well as combinations of these agents together with chemotherapies. Prospective trials currently recruiting participants are testing a diverse range of medical therapies for meningioma, and some studies now require the presence of a specific protein alteration or genetic mutation as an inclusion criterion. Increasing understanding of the unique and heterogeneous nature of meningiomas will continue to spur the development of novel medical therapies for the arsenal against aggressive tumors.

Purpose: Isocitrate dehydrogenase ( IDH ) mutations in glioma patients confer longer survival and may guide treatment decision making. We aimed to predict the IDH status of gliomas from MR imaging by applying a residual convolutional neural network to preoperative radiographic data. Experimental Design: Preoperative imaging was acquired for 201 patients from the Hospital of University of Pennsylvania (HUP), 157 patients from Brigham and Women's Hospital (BWH), and 138 patients from The Cancer Imaging Archive (TCIA) and divided into training, validation, and testing sets. We trained a residual convolutional neural network for each MR sequence (FLAIR, T2, T1 precontrast, and T1 postcontrast) and built a predictive model from the outputs. To increase the size of the training set and prevent overfitting, we augmented the training set images by introducing random rotations, translations, flips, shearing, and zooming. Results: With our neural network model, we achieved IDH prediction accuracies of 82.8% (AUC = 0.90), 83.0% (AUC = 0.93), and 85.7% (AUC = 0.94) within training, validation, and testing sets, respectively. When age at diagnosis was incorporated into the model, the training, validation, and testing accuracies increased to 87.3% (AUC = 0.93), 87.6% (AUC = 0.95), and 89.1% (AUC = 0.95), respectively. Conclusions: We developed a deep learning technique to noninvasively predict IDH genotype in grade II-IV glioma using conventional MR imaging using a multi-institutional data set. Clin Cancer Res; 24(5); 1073-81. ©2017 AACR ., (©2017 American Association for Cancer Research.)

This corrects the article DOI: 10.1038/nature22364.

Purpose of Review: Pituitary tumors are undergoing a transformation in histopathologic and molecular classification, coincident with the continued refinement of increasingly powerful methods of genomic annotation and discovery. We highlight novel genomic alterations identified in pituitary adenomas and craniopharyngiomas and discuss their clinical implications., Recent Findings: Sporadic pituitary adenomas are associated with relatively few recurrent somatic mutations. Recurrent mutations occur largely in subsets of hormone-producing tumors, including GNAS and GPR101 in somatotroph adenomas and USP8 in corticotroph adenomas. Additionally, they manifest with a dichotomous signature of copy number alterations, ranging from almost none to widespread genome instability, while microduplication of chromosome Xq26.3, containing the GNAS gene, defines X-linked acrogigantism. Papillary craniopharyngiomas are defined by BRAF V600E mutations while β-catenin alterations characterize adamantinomatous craniopharyngiomas. Genomic annotation of pituitary tumors is defining increasing subsets of neuroendocrine adenohypophyseal tumors and craniopharyngiomas, offering rationale-based pharmacologic targets and potential biomarkers for clinical outcome.

Question 1: What sequences should be obtained on magnetic resonance imaging (MRI) to evaluate vestibular schwannomas before and after surgery?, Target Population: Adults with vestibular schwannomas., Recommendations: Initial Preoperative Evaluation Level 3: Imaging used to detect vestibular schwannomas should use high-resolution T2-weighted and contrast-enhanced T1-weighted MRI. Level 3: Standard T1, T2, fluid attenuated inversion recovery, and diffusion weighted imaging MR sequences obtained in axial, coronal, and sagittal plane may be used for detection of vestibular schwannomas. Preoperative Surveillance Level 3: Preoperative surveillance for growth of a vestibular schwannoma should be followed with either contrast-enhanced 3-dimensional (3-D) T1 magnetization prepared rapid acquisition gradient echo (MPRAGE) or high-resolution T2 (including constructive interference in steady state [CISS] or fast imaging employing steady-state acquisition [FIESTA] sequences) MRI. Postoperative Evaluation Level 2: Postoperative evaluation should be performed with postcontrast 3-D T1 MPRAGE, with nodular enhancement considered suspicious for recurrence., Question 2: Is there a role for advanced imaging for facial nerve detection preoperatively (eg, CISS/FIESTA or diffusion tensor imaging)?, Target Population: Adults with proven or suspected vestibular schwannomas by imaging., Recommendation: Level 3: T2-weighted MRI may be used to augment visualization of the facial nerve course as part of preoperative evaluation., Question 3: What is the expected growth rate of vestibular schwannomas on MRI, and how often should they be imaged if a "watch and wait" philosophy is pursued?, Target Population: Adults with suspected vestibular schwannomas by imaging., Recommendation: Level 3: MRIs should be obtained annually for 5 yr, with interval lengthening thereafter with tumor stability., Question 4: Do cystic vestibular schwannomas behave differently than their solid counterparts?, Target Population: Adults with vestibular schwannomas with cystic components., Recommendation: Level 3: Adults with cystic vestibular schwannomas should be counseled that their tumors may more often be associated with rapid growth, lower rates of complete resection, and facial nerve outcomes that may be inferior in the immediate postoperative period but similar to noncystic schwannomas over time., Question 5: Should the extent of lateral internal auditory canal involvement be considered by treating physicians?, Target Population: Adult patients with vestibular schwannomas., Recommendation: Level 3: The degree of lateral internal auditory canal involvement by tumor adversely affects facial nerve and hearing outcomes and should be emphasized when interpreting imaging for preoperative planning., Question 6: How should patients with neurofibromatosis type 2 (NF2) and vestibular schwannoma be imaged and over what follow-up period?, Target Population: Adult patients with NF2 and vestibular schwannomas., Recommendation: Level 3: In general, vestibular schwannomas associated with NF2 should be imaged (similar to sporadic schwannomas) with the following caveats: 1. More frequent imaging may be adopted in NF2 patients because of a more variable growth rate for vestibular schwannomas, and annual imaging may ensue once the growth rate is established. 2. In NF2 patients with bilateral vestibular schwannomas, growth rate of a vestibular schwannoma may increase after resection of the contralateral tumor, and therefore, more frequent imaging may be indicated, based on the nonoperated tumor's historical rate of growth. 3. Careful consideration should be given to whether contrast is necessary in follow-up studies or if high-resolution T2 (including CISS or FIESTA-type sequences) MRI may adequately characterize changes in lesion size instead., Question 7: How long should vestibular schwannomas be imaged after surgery, including after gross-total, near-total, and subtotal resection?, Target Population: Adult patients with vestibular schwannomas followed after surgery., Recommendation: Level 3: For patients receiving gross total resection, a postoperative MRI may be considered to document the surgical impression and may occur as late as 1 yr after surgery. For patients not receiving gross total resection, more frequent surveillance scans are suggested; annual MRI scans may be reasonable for 5 yr. Imaging follow-up should be adjusted accordingly for continued surveillance if any change in nodular enhancement is demonstrated.  The full guideline can be found at https://www.cns.org/guidelines/guidelines-management-patients-vestibular-schwannoma/chapter&#95;5., (Copyright © 2017 by the Congress of Neurological Surgeons)

Superior semicircular canal dehiscence (SSCD) syndrome is an increasingly recognized cause of vestibular and/or auditory symptoms in both adults and children. These symptoms are believed to result from the presence of a pathological mobile "third window" into the labyrinth due to deficiency in the osseous shell, leading to inadvertent hydroacoustic transmissions through the cochlea and labyrinth. The most common bony defect of the superior canal is found over the arcuate eminence, with rare cases involving the posteromedial limb of the superior canal associated with the superior petrosal sinus. Operative intervention is indicated for intractable or debilitating symptoms that persist despite conservative management and vestibular sedation. Surgical repair can be accomplished by reconstruction or plugging of the bony defect or reinforcement of the round window through a variety of operative approaches. The authors review the etiology, pathophysiology, presentation, diagnosis, surgical options, and outcomes in the treatment of this entity, with a focus on potential pitfalls that may be encountered during clinical management.

Objectives: 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., Methods: 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)., Results: 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)., Conclusions: 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.

Background: Brain metastases are associated with significant morbidity and mortality. Population-level data describing the incidence and prognosis of patients with brain metastases are lacking. The aim of this study was to characterize the incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy using recently released data from the Surveillance, Epidemiology, and End Results (SEER) program., Methods: We identified 1302166 patients with diagnoses of nonhematologic malignancies originating outside of the CNS between 2010 and 2013 and described the incidence proportion and survival of patients with brain metastases., Results: We identified 26430 patients with brain metastases at diagnosis of cancer. Patients with small cell and non-small cell lung cancer displayed the highest rates of identified brain metastases at diagnosis; among patients presenting with metastatic disease, patients with melanoma (28.2%), lung adenocarcinoma (26.8%), non-small cell lung cancer not otherwise specified/other lung cancer (25.6%), small cell lung cancer (23.5%), squamous cell carcinoma of the lung (15.9%), bronchioloalveolar carcinoma (15.5%), and renal cancer (10.8%) had an incidence proportion of identified brain metastases of >10%. Patients with brain metastases secondary to prostate cancer, bronchioloalveolar carcinoma, and breast cancer displayed the longest median survival (12.0, 10.0, and 10.0 months, respectively)., Conclusions: In this study we provide generalizable estimates of the incidence and prognosis for patients with brain metastases at diagnosis of a systemic malignancy. These data may allow for appropriate utilization of brain-directed imaging as screening for subpopulations with cancer and have implications for clinical trial design and counseling of patients regarding prognosis., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: Meningiomas are the most common primary intracranial tumors in adults. While a majority of meningiomas are slow growing neoplasms that may cured by surgical resection, a subset demonstrates more aggressive behavior and insidiously recurs despite surgery and radiation, without effective alternative treatment options. Elucidation of critical mitogenic pathways in meningioma oncogenesis may offer new therapeutic strategies. We performed an integrated genomic and molecular analysis to characterize the expression and function of osteoglycin (OGN) in meningiomas and explored possible therapeutic approaches for OGN-expressing meningiomas., Methods: OGN mRNA expression in human meningiomas was assessed by RNA microarray and RNAscope. The impact of OGN on cell proliferation, colony formation, and mitogenic signaling cascades was assessed in a human meningioma cell line (IOMM-Lee) with stable overexpression of OGN. Furthermore, the functional consequences of introducing an AKT inhibitor in OGN-overexpressing meningioma cells were assessed., Results: OGN mRNA expression was dramatically increased in meningiomas compared to a spectrum of other brain tumors and normal brain. OGN-overexpressing meningioma cells demonstrated an elevated rate of cell proliferation, cell cycle activation, and colony formation as compared with cells transfected with control vector. In addition, NF2 mRNA and protein expression were both attenuated in OGN-overexpressing cells. Conversely, mTOR pathway and AKT activation increased in OGN-overexpressing cells compared to control cells. Lastly, introduction of an AKT inhibitor reduced OGN expression in meningioma cells and resulted in increased cell death and autophagy, suggestive of a reciprocal relationship between OGN and AKT., Conclusion: We identify OGN as a novel oncogene in meningioma proliferation. AKT inhibition reduces OGN protein levels in meningioma cells, with a concomitant increase in cell death, which provides a promising treatment option for meningiomas with OGN overexpression.

[This corrects the article DOI: 10.1038/s41525-017-0014-7.].

Reddish-purple coloration on the leaf blades and downward rolling of leaf margins are typical symptoms of grapevine leafroll disease (GLD) in red-fruited grapevine cultivars. These typical symptoms are attributed to the expression of genes encoding enzymes for anthocyanins synthesis, and the accumulation of flavonoids in diseased leaves. Drought has been proven to accelerate development of GLD symptoms in virus-infected leaves of grapevine. However, it is not known how drought affects GLD expression nor how anthocyanin biosynthesis in virus-infected leaves is altered. The present study used HPLC to determine the types and levels of anthocyanins, and applied reverse transcription quantitative polymerase chain reaction (RT-qPCR) to analyze the expression of genes encoding enzymes for anthocyanin synthesis. Plantlets of Grapevine leafroll-associated virus 3 (GLRaV-3)-infected Vitis vinifera 'Cabernet Sauvignon' were grown in vitro under PEG-induced drought stress. HPLC found no anthocyanin-related peaks in the healthy plantlets with or without PEG-induced stress, while 11 peaks were detected in the infected plantlets with or without PEG-induced drought stress, but the peaks were significantly higher in infected drought-stressed plantlets. Increased accumulation of total anthocyanin compounds was related to the development of GLD symptoms in the infected plantlets under PEG stress. The highest level of up-regulated gene expression was found in GLRaV-3-infected leaves with PEG-induced drought stress. Analyses of variance and correlation of anthocyanin accumulation with related gene expression levels found that GLRaV-3-infection was the key factor in increased anthocyanin accumulation. This accumulation involved the up-regulation of two key genes, MYBA1 and UFGT, and their expression levels were further enhanced by drought stress.

Background: Cognitive impairment following transsphenoidal surgery (TSS) among patients with pituitary tumors has been intermittently reported and is not well established. We performed a systematic review to summarize the impact of TSS on cognitive function., Methods: We conducted a systematic search of the literature using the PubMed, Cochrane, and Embase databases through October 2014. Studies were selected if they reported cognitive status after surgery and included at least 10 adult patients with pituitary tumors undergoing either endoscopic or microscopic TSS., Results: After removing 69 duplicates, 758 articles were identified, of which 24 were selected for full text review after screening titles and abstracts. After reviewing full texts, nine studies with a combined total of 682 patients were included in the final analysis. Eight studies were cross-sectional and one was longitudinal. These studies used a wide variety of neurocognitive tests to assess memory, attention and executive function post-operatively. Of the eight studies, six reported impairments in verbal and non-verbal memory post-operatively, while others found no association related to memory, and some reported an improvement in episodic, verbal, or logical memory. While four studies found an impaired association between TSS and attention or executive function, another four studies did not., Conclusion: The current literature on cognitive impairments after TSS is limited and inconsistent. This review demonstrates that patients undergoing TSS may experience a variety of effects on executive function and memory post-operatively, but changes in verbal memory are most common., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Melanoma is the most lethal of skin cancers, in part because of its proclivity for rapid and distant metastasis. It is also potentially the most neurotropic cancer in terms of probability of CNS metastasis from the primary lesion. Despite surgical resection and radiotherapy, prognosis remains guarded for patients with brain metastases. Over the past five years, a new domain of personalized therapy has emerged for advanced melanoma patients with the introduction of BRAF and other MAP kinase pathway inhibitors, immunotherapy, and combinatory therapeutic strategies. By targeting critical cellular signaling pathways and unleashing the adaptive immune response against tumor antigens, a subset of melanoma patients have demonstrated remarkable responses to these treatments. Over time, acquired resistance to these modalities inexorably develops, providing new challenges to overcome. We review the rapidly evolving terrain for intracranial melanoma treatment, address likely and potential mechanisms of resistance, as well as evaluate promising future therapeutic approaches currently under clinical investigation., Competing Interests: CONFLICTS OF INTEREST None.

Background: Clinical genomics platforms are needed to identify targetable alterations, but implementation of these technologies and best practices in routine clinical pediatric oncology practice are not yet well established., Methods: Profile is an institution-wide prospective clinical research initiative that uses targeted sequencing to identify targetable alterations in tumors. OncoPanel, a multiplexed targeted exome-sequencing platform that includes 300 cancer-causing genes, was used to assess single nucleotide variants and rearrangements/indels. Alterations were annotated (Tiers 1-4) based on clinical significance, with Tier 1 alterations having well-established clinical utility. OncoCopy, a clinical genome-wide array comparative genomic hybridization (aCGH) assay, was also performed to evaluate copy number alterations and better define rearrangement breakpoints., Results: Cancer genomes of 203 pediatric brain tumors were profiled across histological subtypes, including 117 samples analyzed by OncoPanel, 146 by OncoCopy, and 60 tumors subjected to both methodologies. OncoPanel revealed clinically relevant alterations in 56% of patients (44 cancer mutations and 20 rearrangements), including BRAF alterations that directed the use of targeted inhibitors. Rearrangements in MYB-QKI, MYBL1, BRAF, and FGFR1 were also detected. Furthermore, while copy number profiles differed across histologies, the combined use of OncoPanel and OncoCopy identified subgroup-specific alterations in 89% (17/19) of medulloblastomas., Conclusion: The combination of OncoPanel and OncoCopy multiplex genomic assays can identify critical diagnostic, prognostic, and treatment-relevant alterations and represents an effective precision medicine approach for clinical evaluation of pediatric brain tumors., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)