Showing papers in "Neuro-oncology in 2017"

GlioVis data portal for visualization and analysis of brain tumor expression datasets.

Abstract: © The Author(s) 2016. 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. doi:10.1093/neuonc/now199 Advance Access date 14 September 2016 the effects they observed could be influenced by inhibition of other types of Trk receptors or signaling molecules downstream of Trk. We have recently started a series of experiments aiming to verify whether specific TrkB inhibition reduces glioma cell proliferation using ANA-12, a small-molecule selective TrkB antagonist. Our first results showed that ANA-12 effectively and dose-dependently reduces the viability of a human glioblastoma cell line with almost complete disappearance of cultured cells 72 hours after treatment (Fig. 1). Therefore, selective TrkB inhibition might prove to be an effective experimental therapeutic strategy, possibly with fewer off-target toxicities compared with multitarget drugs in patients with astrocytomas harboring oncogenic TrkB.

Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study.

Abstract: 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.

Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO).

Abstract: The management of patients with brain metastases has become a major issue due to the increasing frequency and complexity of the diagnostic and therapeutic approaches. In 2014, the European Association of Neuro-Oncology (EANO) created a multidisciplinary Task Force to draw evidence-based guidelines for patients with brain metastases from solid tumors. Here, we present these guidelines, which provide a consensus review of evidence and recommendations for diagnosis by neuroimaging and neuropathology, staging, prognostic factors, and different treatment options. Specifically, we addressed options such as surgery, stereotactic radiosurgery/stereotactic fractionated radiotherapy, whole-brain radiotherapy, chemotherapy and targeted therapy (with particular attention to brain metastases from non-small cell lung cancer, melanoma and breast and renal cancer), and supportive care.

Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy

Abstract: Background Despite a multiplicity of clinical trials testing immune checkpoint inhibitors, the frequency of expression of potential predictive biomarkers is unknown in glioma. Methods In this study, we profiled the frequency of shared biomarker phenotypes. To clarify the relationships among tumor mutational load (TML), mismatch repair (MMR), and immune checkpoint expression, we profiled patients with glioma (n = 327), including glioblastoma (GBM) (n = 198), whose samples had been submitted for analysis from 2009 to 2016. The calculation algorithm for TML included nonsynonymous mutation counts per tumor, with germline mutations filtered out. Immunohistochemical analysis and next-generation sequencing were used to determine tumor-infiltrating lymphocyte expression positive for programmed cell death protein 1 (PD-1), PD ligand 1 (PD-L1) expression on tumor cells, MMR (MLH1, MSH2, MSH6, and PMS2) protein expression and mutations, and DNA polymerase epsilon (POLE) mutations. Results High TML was only found in 3.5% of GBM patients (7 of 198) and was associated with the absence of protein expression of mutL homolog 1 (MLH1) (P = .0345), mutS homolog 2 (MSH2) (P = .0099), MSH6 (P = .0022), and postmeiotic segregation increased 2 (PMS2) (P = .0345) and the presence of DNA MMR mutations. High and moderate TML GBMs did not have an enriched influx of CD8+ T cells, PD-1+ T cells, or tumor-expressed PD-L1. IDH1 mutant gliomas were not enriched for high TML, PD-1+ T cells, or PD-L1 expression. Conclusions To clarify the relationships among TML, MMR, and immune checkpoint expression, we profiled the frequency of shared biomarker phenotypes. On the basis of a variety of potential biomarkers of response to immune checkpoints, only small subsets of glioma patients are likely to benefit from monotherapy immune checkpoint inhibition.

MRI features predict survival and molecular markers in diffuse lower-grade gliomas.

Abstract: Background Previous studies have shown that MR imaging features can be used to predict survival and molecular profile of glioblastoma. However, no study of a similar type has been performed on lower-grade gliomas (LGGs). Methods Presurgical MRIs of 165 patients with diffuse low- and intermediate-grade gliomas (histological grades II and III) were scored according to the Visually Accessible Rembrandt Images (VASARI) annotations. Radiomic models using automated texture analysis and VASARI features were built to predict isocitrate dehydrogenase 1 (IDH1) mutation, 1p/19q codeletion status, histological grade, and tumor progression. Results Interrater analysis showed significant agreement in all imaging features scored (k = 0.703-1.000). On multivariate Cox regression analysis, no enhancement and a smooth non-enhancing margin were associated with longer progression-free survival (PFS), while a smooth non-enhancing margin was associated with longer overall survival (OS) after taking into account age, grade, tumor location, histology, extent of resection, and IDH1 1p/19q subtype. Using logistic regression and bootstrap testing evaluations, texture models were found to possess higher prediction potential for IDH1 mutation, 1p/19q codeletion status, histological grade, and progression of LGGs than VASARI features, with areas under the receiver-operating characteristic curves of 0.86 ± 0.01, 0.96 ± 0.01, 0.86 ± 0.01, and 0.80 ± 0.01, respectively. Conclusion No enhancement and a smooth non-enhancing margin on MRI were predictive of longer PFS, while a smooth non-enhancing margin was a significant predictor of longer OS in LGGs. Textural analyses of MR imaging data predicted IDH1 mutation, 1p/19q codeletion, histological grade, and tumor progression with high accuracy.

A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study

Abstract: Background Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG. Methods Selumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed during the first course. BRAF aberrations in tumor tissue were determined by real-time polymerase chain reaction and fluorescence in situ hybridization. Results Thirty-eight eligible subjects were enrolled. Dose levels 1 and 2 (33 and 43 mg/m2/dose b.i.d.) were excessively toxic. DLTs included grade 3 elevated amylase/lipase (n = 1), headache (n = 1), mucositis (n = 2), and grades 2-3 rash (n = 6). At dose level 0 (25 mg/m2/dose b.i.d, the RP2D), only 3 of 24 subjects experienced DLTs (elevated amylase/lipase, rash, and mucositis). At the R2PD, the median (range) area under the curve (AUC0-∞) and apparent oral clearance of selumetinib were 3855 ng*h/mL (1780 to 7250 ng × h/mL) and 6.5 L × h-1 × m-2 (3.4 to 14.0 L × h-1 × m-2), respectively. Thirteen of 19 tumors had BRAF abnormalities. Among the 5 (20%) of 25 subjects with sustained partial responses, all at the RP2D, 4 had BRAF aberrations, 1 had insufficient tissue. Subjects received a median of 13 cycles (range: 1-26). Fourteen (37%) completed all protocol treatment (26 cycles [n = 13], 13 cycles [n = 1]) with at least stable disease; 2-year progression-free survival at the RP2D was 69 ± SE 9.8%. Conclusion Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.

Multimodal MRI features predict isocitrate dehydrogenase genotype in high-grade gliomas

Abstract: Background High-grade gliomas with mutations in the isocitrate dehydrogenase (IDH) gene family confer longer overall survival relative to their IDH-wild-type counterparts. Accurate determination of the IDH genotype preoperatively may have both prognostic and diagnostic value. The current study used a machine-learning algorithm to generate a model predictive of IDH genotype in high-grade gliomas based on clinical variables and multimodal features extracted from conventional MRI. Methods Preoperative MRIs were obtained for 120 patients with primary grades III (n = 35) and IV (n = 85) glioma in this retrospective study. IDH genotype was confirmed for grade III (32/35, 91%) and IV (22/85, 26%) tumors by immunohistochemistry, spectrometry-based mutation genotyping (OncoMap), or multiplex exome sequencing (OncoPanel). IDH1 and IDH2 mutations were mutually exclusive, and all mutated tumors were collapsed into one IDH-mutated cohort. Cases were randomly assigned to either the training (n = 90) or validation cohort (n = 30). A total of 2970 imaging features were extracted from pre- and postcontrast T1-weighted, T2-weighted, and apparent diffusion coefficient map. Using a random forest algorithm, nonredundant features were integrated with clinical data to generate a model predictive of IDH genotype. Results Our model achieved accuracies of 86% (area under the curve [AUC] = 0.8830) in the training cohort and 89% (AUC = 0.9231) in the validation cohort. Features with the highest predictive value included patient age as well as parametric intensity, texture, and shape features. Conclusion Using a machine-learning algorithm, we achieved accurate prediction of IDH genotype in high-grade gliomas with preoperative clinical and MRI features.

The impact of surgery in molecularly defined low-grade glioma: an integrated clinical, radiological, and molecular analysis.

Abstract: _Background_ Extensive resections in low-grade glioma (LGG) are associated with improved overall survival (OS). However, World Health Organization (WHO) classification of gliomas has been completely revised and is now predominantly based on molecular criteria. This requires reevaluation of the impact of surgery in molecularly defined LGG subtypes. _Methods_ We included 228 adults who underwent surgery since 2003 for a supratentorial LGG. Pre- and postoperative tumor volumes were assessed with semiautomatic software on T2-weighted images. Targeted next-generation sequencing was used to classify samples according to current WHO classification. Impact of postoperative volume on OS, corrected for molecular profile, was assessed using a Cox proportional hazards model. _Results_ Median follow-up was 5.79 years. In 39 (17.1%) histopathologically classified gliomas, the subtype was revised after molecular analysis. Complete resection was achieved in 35 patients (15.4%), and in 54 patients (23.7%) only small residue (0.1-5.0 cm 3) remained. In multivariable analysis, postoperative volume was associated with OS, with a hazard ratio of 1.01 (95% CI: 1.002-1.02; P = 0.016) per cm 3 increase in volume. The impact of postoperative volume was particularly strong in isocitrate dehydrogenase (IDH) mutated astrocytoma patients, where even very small postoperative volumes (0.1-5.0 cm) already negatively affected OS. _Conclusion_ Our data provide the necessary reevaluation of the impact of surgery in molecularly defined LGG and support maximal resection as first-line treatment for molecularly defined LGG. Importantly, in IDH mutated astrocytoma, even small postoperative volumes have negative impact on OS, which argues for a second-look operation in this subtype to remove minor residues if safely possible.

Correlation of immune phenotype with IDH mutation in diffuse glioma.

Abstract: Tumor infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) are targets of immune checkpoint inhibitors Forty-three World Health Organization (WHO) grade II/III gliomas (39 IDH-mutant [mut], 4 IDH-wildtype [wt]) and 14 IDH-mut glioblastomas (GBM) were analyzed for TIL (CD3+; PD1+) infiltration and PD-L1 expression Results were compared with the data of a previously published series of 117 IDH-wt glioblastomas PD-L1 gene expression levels were evaluated in 677 diffuse gliomas grades II-IV from The Cancer Genome Atlas (TCGA) database TIL and PD-L1 expression were observed in approximately half of WHO grade II/III gliomas IDH-wt status was associated with significantly higher TIL infiltration and PD-L1 expression among all (grades II-IV) cases (n = 174, P < 0001) and within the cohort of glioblastomas (n = 131, P < 0001) In low-grade glioma (LGG) and glioblastoma cohorts of TCGA, significantly higher PD-L1 gene expression levels were evident in IDH-wt compared with IDH-mut samples (LGG: N = 516; P = 1933e-11, GBM: N = 161; P < 0009) Lower PD-L1 gene expression was associated with increased promoter methylation (Spearman correlation coefficient -036; P < 001) in the LGG cohort of TCGA IDH-mut gliomas had higher PD-L1 gene promoter methylation levels than IDH-wt gliomas (P < 001) The immunological tumor microenvironment of diffuse gliomas differs in association with IDH mutation status IDH-wt gliomas display a more prominent TIL infiltration and higher PD-L1 expression than IDH-mut cases Mechanistically this may be at least in part due to differential PD-L1 gene promoter methylation levels Our findings may be relevant for immune modulatory treatment strategies in glioma patients

Characteristics of H3 K27M-mutant gliomas in adults.

Abstract: Background Diffuse H3 K27M-mutant gliomas occur primarily in children but can also be encountered in adults. The aim of this study was to describe the characteristics of H3 K27M-mutant gliomas in adults. Methods We analyzed the characteristics of 21 adult H3 K27M-mutant gliomas and compared them with those of 135 adult diffuse gliomas without histone H3 and without isocitrate dehydrogenase (IDH) mutation (IDH/H3 wild type). Results The median age at diagnosis in H3 K27M-mutant gliomas was 32 years (range: 18-82 y). All tumors had a midline location (spinal cord n = 6, thalamus n = 5, brainstem n = 5, cerebellum n = 3, hypothalamus n = 1, and pineal region n = 1) and were IDH and BRAF-V600E wild type. The identification of an H3 K27M mutation significantly impacted the diagnosis in 3 patients (14%) for whom the histological aspect initially suggested a diffuse low-grade glioma and in 7 patients (33%) for whom pathological analysis hesitated between a diffuse glioma, ganglioglioma, or pilocytic astrocytoma. Compared with IDH/H3 wild-type gliomas, H3 K27M-mutant gliomas were diagnosed at an earlier age (32 vs 64 y, P < .001), always had a midline location (21/21 vs 21/130, P < .001), less frequently had a methylated MGMT promoter (1/21 vs 52/129, P = .002), and lacked EGFR amplification (0/21 vs 26/128, P = .02). The median survival was 19.6 months in H3 K27M-mutant gliomas and 17 months in IDH/H3 wild-type gliomas (P = .3). Conclusion In adults, as in children, H3 K27M mutations define a distinct subgroup of IDH wild-type gliomas characterized by a constant midline location, low rate of MGMT promoter methylation, and poor prognosis.

MR perfusion-weighted imaging in the evaluation of high-grade gliomas after treatment: a systematic review and meta-analysis.

Abstract: BACKGROUND Distinction between tumor and treatment related changes is crucial for clinical management of patients with high-grade gliomas. Our purpose was to evaluate whether dynamic susceptibility contrast-enhanced (DSC) and dynamic contrast enhanced (DCE) perfusion-weighted imaging (PWI) metrics can effectively differentiate between recurrent tumor and posttreatment changes within the enhancing signal abnormality on conventional MRI. METHODS A comprehensive literature search was performed for studies evaluating PWI-based differentiation of recurrent tumor and posttreatment changes in patients with high-grade gliomas (World Health Organization grades III and IV). Only studies published in the "temozolomide era" beginning in 2005 were included. Summary estimates of diagnostic accuracy were obtained by using a random-effects model. RESULTS Of 1581 abstracts screened, 28 articles were included. The pooled sensitivities and specificities of each study's best performing parameter were 90% and 88% (95% CI: 0.85-0.94; 0.83-0.92) and 89% and 85% (95% CI: 0.78-0.96; 0.77-0.91) for DSC and DCE, respectively. The pooled sensitivities and specificities for detecting tumor recurrence using the 2 most commonly evaluated parameters, mean relative cerebral blood volume (rCBV) (threshold range, 0.9-2.15) and maximum rCBV (threshold range, 1.49-3.1), were 88% and 88% (95% CI: 0.81-0.94; 0.78-0.95) and 93% and 76% (95% CI: 0.86-0.98; 0.66-0.85), respectively. CONCLUSIONS PWI-derived thresholds separating viable tumor from treatment changes demonstrate relatively good accuracy in individual studies. However, because of significant variability in optimal reported thresholds and other limitations in the existing body of literature, further investigation and standardization is needed before implementing any particular quantitative PWI strategy across institutions.

Tumor microtubes convey resistance to surgical lesions and chemotherapy in gliomas

Abstract: Background Primary and adaptive resistance against chemo- and radiotherapy and local recurrence after surgery limit the benefits from these standard treatments in glioma patients. Recently we found that glioma cells can extend ultra-long membrane protrusions, "tumor microtubes" (TMs), for brain invasion, proliferation, and interconnection of single cells to a syncytium that is resistant to radiotherapy. We wondered whether TMs also convey resistance to the other 2 standard treatment modalities. Methods Patient-derived glioblastoma stemlike cell (GBMSC) lines were implanted under a cranial window in mice. Longitudinal in vivo two-photon laser scanning microscopy was used to follow tumor growth, including the fate of single glioma cells over months. Results After a cylindrical surgical lesion, GBMSCs increasingly extended TMs toward the lesion area, which contributed to the repopulation of this area over many weeks. In fact, an excessive "healing response" was observed in which tumor cell densities significantly exceeded those of unlesioned brain regions over time. Inhibition of TM formation and function by genetic targeting of growth associated protein-43 robustly suppressed this surgery-induced tumor growth reaction, in contrast to standard postsurgical anti-inflammatory treatment with dexamethasone. After one cycle of temozolomide chemotherapy, intra- and intertumoral heterogeneity of TM formation and interconnection was strongly associated with therapy response: when tumor cells were integrated in TM networks, they were more likely to resist chemotherapy. Conclusion TMs can contribute to the resistance against standard treatment modalities in gliomas. Specific inhibition of TMs is a promising approach to reduce local recurrence after surgery and lower resistance to chemotherapy.

Adult IDH wild-type lower-grade gliomas should be further stratified.

Abstract: Background Astrocytoma of the isocitrate dehydrogenase (IDH) wild-type gene is described as a provisional entity within the new World Health Organization (WHO) classification. Some groups believe that IDH wild-type lower-grade gliomas, when interrogated for other biomarkers, will mostly turn out to be glioblastoma. We hypothesize that not all IDH wild-type lower-grade gliomas have very poor outcomes and the group could be substratified prognostically. Methods Seven hundred and eighteen adult WHO grades II and III patients with gliomas from our hospitals were re-reviewed and tested for IDH1/2 mutations. One hundred and sixty-six patients with IDH wild-type cases were identified for further studies, and EGFR and MYB amplifications, mutations of histone H3F3A, TERT promoter (TERTp), and BRAF were examined. Results EGFR amplification, BRAF, and H3F3A mutations were observed in 13.8%, 6.9%, and 9.5% of patients, respectively, in a mutually exclusive pattern in IDH wild-type lower-grade gliomas. TERTp mutations were detected in 26.8% of cases. Favorable outcome was observed in patients with young age, oligodendroglial phenotype, and grade II histology. Independent adverse prognostic values of older age, nontotal resection, grade III histology, EGFR amplification, and H3F3A mutation were confirmed by multivariable analysis. Tumors were further classified into "molecularly" high grade (harboring EGFR, H3F3A, or TERTp) (median overall survival = 1.23 y) and lower grade (lacking all of the 3) (median overall survival = 7.63 y) with independent prognostic relevance. The most favorable survival was noted in molecularly lower-grade gliomas with MYB amplification. Conclusion Adult IDH wild-type lower-grade gliomas are prognostically heterogeneous and do not have uniformly poor prognosis. Clinical information and additional markers, including MYB, EGFR, TERTp, and H3F3A, should be examined to delineate discrete favorable and unfavorable prognostic groups.

Hypoxia in the glioblastoma microenvironment: shaping the phenotype of cancer stem-like cells.

Abstract: Glioblastoma is the most common and aggressive malignant primary brain tumor. Cellular heterogeneity is a characteristic feature of the disease and contributes to the difficulty in formulating effective therapies. Glioma stem-like cells (GSCs) have been identified as a subpopulation of tumor cells that are thought to be largely responsible for resistance to treatment. Intratumoral hypoxia contributes to maintenance of the GSCs by supporting the critical stem cell traits of multipotency, self-renewal, and tumorigenicity. This review highlights the interaction of GSCs with the hypoxic tumor microenvironment, exploring the mechanisms underlying the contribution of GSCs to tumor vessel dynamics, immune modulation, and metabolic alteration.

Systemic therapy of brain metastases: non-small cell lung cancer, breast cancer, and melanoma.

Abstract: Brain metastases (BM) occur frequently in many cancers, particularly non-small cell lung cancer (NSCLC), breast cancer, and melanoma. The development of BM is associated with poor prognosis and has an adverse impact on survival and quality of life. Commonly used therapies for BM such as surgery or radiotherapy are associated with only modest benefits. However, recent advances in systemic therapy of many cancers have generated considerable interest in exploration of those therapies for treatment of intracranial metastases.This review discusses the epidemiology of BM from the aforementioned primary tumors and the challenges of using systemic therapies for metastatic disease located within the central nervous system. Cumulative data from several retrospective and small prospective studies suggest that molecularly targeted systemic therapies may be an effective option for the treatment of BM from NSCLC, breast cancer, and melanoma, either as monotherapy or in conjunction with other therapies. Larger prospective studies are warranted to further characterize the efficacy and safety profiles of these targeted agents for the treatment of BM.

PET imaging in patients with meningioma - Report of the RANO/PET Group

Abstract: Meningiomas are the most frequent nonglial primary brain tumors and represent about 30% of brain tumors. Usually, diagnosis and treatment planning are based on neuroimaging using mainly MRI or, rarely, CT. Most common treatment options are neurosurgical resection and radiotherapy (eg, radiosurgery, external fractionated radiotherapy). For follow-up after treatment, a structural imaging technique such as MRI or CT is used. However, these structural imaging modalities have limitations, particularly in terms of tumor delineation as well as diagnosis of posttherapeutic reactive changes. Molecular imaging techniques such as PET can characterize specific metabolic and cellular features which may provide clinically relevant information beyond that obtained from structural MR or CT imaging alone. Currently, the use of PET in meningioma patients is steadily increasing. In the present article, we provide recommendations for the use of PET imaging in the clinical management of meningiomas based on evidence generated from studies being validated by histology or clinical course.

Global incidence of malignant brain and other central nervous system tumors by histology, 2003–2007

Abstract: Background Previous reports have shown that overall incidence of malignant brain and other central nervous system (CNS) tumors varied significantly by country. The aim of this study was to estimate histology-specific incidence rates by global region and assess incidence variation by histology and age. Methods Using data from the Central Brain Tumor Registry of the United States (CBTRUS) and the International Agency for Research on Cancer's (IARC) Cancer Incidence in Five Continents X (including over 300 cancer registries), we calculated the age-adjusted incidence rates (AAIR) per 100000 person-years and 95% CIs for brain and other CNS tumors overall and by age groups and histology. Results There were significant differences in incidence by region. Overall incidence of malignant brain tumors per 100000 person-years in the US was 5.74 (95% CI = 5.71-5.78). Incidence was lowest in Southeast Asia (AAIR = 2.55, 95% CI = 2.44-2.66), India (AAIR = 2.85, 95% CI = 2.78-2.93), and East Asia (AAIR = 3.07, 95% CI = 3.02-3.12). Incidence was highest in Northern Europe (AAIR = 6.59, 95% CI = 6.52-6.66) and Canada (AAIR = 6.53, 95% CI = 6.41-6.66). Astrocytic tumors showed the broadest variation in incidence regionally across the globe. Conclusion Brain and other CNS tumors are a significant source of cancer-related morbidity and mortality worldwide. Regional differences in incidence may provide clues toward genetic or environmental causes as well as a foundation for broadening knowledge of their epidemiology. Gaining a comprehensive understanding of the epidemiology of malignant brain tumors globally is critical to researchers, public health officials, disease interest groups, and clinicians and contributes to collaborative efforts in future research.

Detection of wild-Type EGFR amplification and EGFRvIII mutation in CSF-derived extracellular vesicles of glioblastoma patients

Abstract: Background RNAs within extracellular vesicles (EVs) have potential as diagnostic biomarkers for patients with cancer and are identified in a variety of biofluids. Glioblastomas (GBMs) release EVs containing RNA into cerebrospinal fluid (CSF). Here we describe a multi-institutional study of RNA extracted from CSF-derived EVs of GBM patients to detect the presence of tumor-associated amplifications and mutations in epidermal growth factor receptor (EGFR). Methods CSF and matching tumor tissue were obtained from patients undergoing resection of GBMs. We determined wild-type (wt)EGFR DNA copy number amplification, as well as wtEGFR and EGFR variant (v)III RNA expression in tumor samples. We also characterized wtEGFR and EGFRvIII RNA expression in CSF-derived EVs. Results EGFRvIII-positive tumors had significantly greater wtEGFR DNA amplification (P = 0.02) and RNA expression (P = 0.03), and EGFRvIII-positive CSF-derived EVs had significantly more wtEGFR RNA expression (P = 0.004). EGFRvIII was detected in CSF-derived EVs for 14 of the 23 EGFRvIII tissue-positive GBM patients. Conversely, only one of the 48 EGFRvIII tissue-negative patients had the EGFRvIII mutation detected in their CSF-derived EVs. These results yield a sensitivity of 61% and a specificity of 98% for the utility of CSF-derived EVs to detect an EGFRvIII-positive GBM. Conclusion Our results demonstrate CSF-derived EVs contain RNA signatures reflective of the underlying molecular genetic status of GBMs in terms of wtEGFR expression and EGFRvIII status. The high specificity of the CSF-derived EV diagnostic test gives us an accurate determination of positive EGFRvIII tumor status and is essentially a less invasive "liquid biopsy" that might direct mutation-specific therapies for GBMs.

Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma

Abstract: Background Adaptive immune resistance in the tumor microenvironment appears to attenuate the immunotherapeutic targeting of glioblastoma (GBM). In this study, we identified a tumor-infiltrating myeloid cell (TIM) population that expands in response to dendritic cell (DC) vaccine treatment. The aim of this study was to understand how this programmed death ligand 1 (PD-L1)-expressing population restricts activation and tumor-cytolytic function of vaccine-induced tumor-infiltrating lymphocytes (TILs). Methods To test this hypothesis in our in vivo preclinical model, we treated mice bearing intracranial gliomas with DC vaccination ± murine anti-PD-1 monoclonal antibody (mAb) blockade or a colony stimulating factor 1 receptor inhibitor (CSF-1Ri) (PLX3397) and measured overall survival. We then harvested and characterized the PD-L1+ TIM population and its role in TIL activation and tumor cytolysis in vitro. Results Our data indicated that the majority of PD-L1 expression in the GBM environment is contributed by TIMs rather than by tumor cells themselves. While PD-1 blockade partially reversed the TIL dysfunction, targeting TIMs directly with CSF-1Ri altered TIM expression of key chemotactic factors associated with promoting increased TIL infiltration after vaccination. Neither PD-1 mAb nor CSF-1Ri had a demonstrable therapeutic benefit alone, but when combined with DC vaccination, a significant survival benefit was observed. When the tripartite regimen was given (DC vaccine, PD-1 mAb, PLX3397), long-term survival was noted together with an increase in the number of TILs and TIL activation. Conclusion Together, these studies elucidate the role that TIMs play in mediating adaptive immune resistance in the GBM microenvironment and provide evidence that they can be manipulated pharmacologically with agents that are clinically available. Development of immune resistance in response to active vaccination in GBM can be reversed with dual administration of CSF-1Ri and PD-1 mAb.

Outcome of patients with intracranial non-germinomatous germ cell tumors-lessons from the SIOP-CNS-GCT-96 trial

Abstract: Background Following promising results to increase survival and reduce treatment burden in intracranial non-germinomatous germ cell tumors (NGGCTs), we conducted a European study using dose-intense chemotherapy followed by risk-adapted radiotherapy. Methods All patients received 4 courses of cisplatin/etoposide/ifosfamide. Non-metastatic patients then received focal radiotherapy only (54 Gy); metastatic patients received 30 Gy craniospinal radiotherapy with 24 Gy boost to primary tumor and macroscopic metastatic sites. Results Patients with localized malignant NGGCT (n = 116) demonstrated 5-year progression-free survival (PFS) and overall survival (OS) of 0.72 ± 0.04 and 0.82 ± 0.04, respectively. Primary tumor sites were: 67 pineal, 35 suprasellar, 5 bifocal, 9 others. One patient died postsurgery in clinical remission; 3 patients progressed during treatment and 27 (23%) relapsed afterward. Fourteen were local, 6 combined, and 7 distant relapses (outside radiation field). Seventeen of the 27 relapsed patients died of disease. Patients with metastatic disease (n = 33) demonstrated 5-year PFS and OS of 0.68 ± 0.09 and 0.75 ± 0.08, respectively; 1 patient died following progression on treatment and 9 (27%) relapsed afterward (5 local, 1 combined, 3 distant). Only one metastatic patient with recurrence was salvaged. Multivariate analysis identified diagnostic alpha-fetoprotein level (serum and/or cerebrospinal fluid level >1000 ng/mL, 19/149 patients, of whom 11 relapsed; P < 0.0003) and residual disease following treatment, including after second-look surgery (n = 52/145 evaluable patients, 26 relapsed; P = 0.0002) as significant prognostic indicators in this cohort. Conclusion In localized malignant NGGCT, craniospinal radiotherapy could be avoided without increased relapses outside the radiotherapy field. Chemotherapy and craniospinal radiotherapy remain the gold standard for metastatic disease.

Phase i study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma

Abstract: Background: Sonidegib (LDE225) is a potent, selective hedgehog (Hh) inhibitor of Smoothened. This study explored the safety and pharmacokinetics of sonidegib in children with relapsed/recurrent tumors followed by a phase II trial in pediatric and adult patients with relapsed medulloblastoma (MB) to assess tumor response. Methods: Pediatric patients aged ≥1 to <18 years were included according to a Bayesian design starting at 372 mg/m2 of continuous once daily oral sonidegib. Tumor samples were analyzed for Hh pathway activation using a validated 5-gene Hh signature assay. In phase II, pediatric patients were treated at the recommended phase II dose (RP2D) while adults received 800 mg daily. Results: Sixteen adult (16 MB) and 60 pediatric (39 MB, 21 other) patients with an age range of 2-17 years were enrolled. The RP2D of sonidegib in pediatric patients was established at 680 mg/m2 once daily. The phase II study was closed prematurely. The 5-gene Hh signature assay showed that the 4 complete responders (2 pediatric and 2 adult) and 1 partial responder (adult) all had Hh-activated tumors, while 5 patients with activated Hh had either stable disease (n = 3) or progressive disease (n = 2). No patient with an Hh-negative signature (n = 50) responded. The safety profile for pediatric patients was generally consistent with the one established for adult patients; however, growth plate changes were observed in prepubertal pediatric patients. Conclusions: Sonidegib was well tolerated and the RP2D in pediatric patients was 680 mg/m2 once daily. Five of the 10 MB patients with activated Hh pathway demonstrated complete or partial responses.

The contribution of tumor-Associated macrophages in glioma neo-Angiogenesis and implications for anti-Angiogenic strategies

Abstract: "Tumor-associated macrophages" (TAMs) form a significant cell population in malignant tumors and contribute to tumor growth, metastasis, and neovascularization. Gliomas are characterized by extensive neo-angiogenesis, and knowledge of the role of TAMs in neovascularization is important for future anti-angiogenic therapies. The phenotypes and functions of TAMs are heterogeneous and more complex than a classification into M1 and M2 inflammation response types would suggest. In this review, we provide an update on the current knowledge of the ontogeny of TAMs, focusing on diffuse gliomas. The role of TAMs in the regulation of the different processes in tumor angiogenesis is highlighted and the most recently discovered mechanisms by which TAMs mediate resistance against current antivascular therapies are mentioned. Novel compounds tested in clinical trials are discussed and brought in relation to different TAM-related angiogenesis pathways. In addition, potential therapeutic targets used to intervene in TAM-regulated tumor angiogenesis are summarized.

A clinical perspective on the 2016 WHO brain tumor classification and routine molecular diagnostics

Abstract: The 2007 World Health Organization (WHO) classification of brain tumors did not use molecular abnormalities as diagnostic criteria. Studies have shown that genotyping allows a better prognostic classification of diffuse glioma with improved treatment selection. This has resulted in a major revision of the WHO classification, which is now for adult diffuse glioma centered around isocitrate dehydrogenase (IDH) and 1p/19q diagnostics. This revised classification is reviewed with a focus on adult brain tumors, and includes a recommendation of genes of which routine testing is clinically useful. Apart from assessment of IDH mutational status including sequencing of R132H-immunohistochemistry negative cases and testing for 1p/19q, several other markers can be considered for routine testing, including assessment of copy number alterations of chromosome 7 and 10 and of TERT promoter, BRAF, and H3F3A mutations. For "glioblastoma, IDH mutated" the term "astrocytoma grade IV" could be considered. It should be considered to treat IDH wild-type grades II and III diffuse glioma with polysomy of chromosome 7 and loss of 10q as glioblastoma. New developments must be more quickly translated into further revised diagnostic categories. Quality control and rapid integration of molecular findings into the final diagnosis and the communication of the final diagnosis to clinicians require systematic attention.

Blocking MIR155HG/miR-155 axis inhibits mesenchymal transition in glioma.

Abstract: Background MIR155 host gene (MIR155HG) is a long noncoding RNA that has been considered as the primary micro (mi)RNA of miR-155. MIR155HG plays an essential role in hematopoiesis, inflammation, and tumorigenesis. Our study investigated the clinical significance, biological function, mechanisms, and small-molecule inhibitors of the MIR155HG/miR-155 axis in glioma. Methods We analyzed the expression of the MIR155HG/miR-155 axis and the correlation with glioma grade and patient survival using 2 different glioma gene expression datasets. Biological significance was elucidated through a series of in vitro and in vivo experiments. Furthermore, we conducted a high-throughput screening for small molecules to identify a potential inhibitor of the MIR155HG/miR-155 axis. Results Increased MIR155HG was associated with glioma grade, mesenchymal transition, and poor prognosis. Functionally, MIR155HG reduction by small interfering RNA inhibited cell proliferation, migration, invasion, and orthotopic glioma growth by repressing the generation of its derivatives miR-155-5p and miR-155-3p. Bioinformatics and luciferase reporter assays revealed that protocadherin 9 and protocadherin 7, which act as tumor suppressors by inhibiting the Wnt/β-catenin pathway, were direct targets of miR-155-5p and miR-155-3p, respectively. Finally, we identified NSC141562 as a potent small-molecule inhibitor of the MIR155HG/miR-155 axis. Conclusions Our results demonstrate that the MIR155HG/miR-155 axis plays a critical role in facilitating glioma progression and serves as a prognostic factor for patient survival in glioblastoma. High-throughput screening indicated that the MIR155HG/miR-155 axis inhibitor NSC141562 may be a useful candidate anti-glioma drug.

miR-423-5p contributes to a malignant phenotype and temozolomide chemoresistance in glioblastomas.

Abstract: Background Gliomas are based on a genetic abnormality and present with a dismal prognosis. MicroRNAs (miRNAs) are considered to be important mediators of gene expression in glioma tissues. Methods Real-time PCR was used to analyze the expression of microRNA-423-5p (miR-423-5p) in human glioma samples and normal brain tissue. Apoptosis, cell cycle, proliferation, immunostaining, transwell, in vitro 2D and 3D migration, and chemosensitivity assays were performed to assess the phenotypic changes in glioma cells overexpressing miRNA-423-5p. Western blotting was used to determine the expression of inhibitor of growth 4 (ING-4)in glioma tissues, and a luciferase reporter assay was conducted to confirm whether ING-4 is a direct target of miR-423-5p. Western blotting was used to identify the potential signaling pathways that are affected in glioma cell growth by miR-423-5p. Xenograft tumors were examined in vivo for the carcinogenic effects of miR-423-5p in glioma tissues. Results We first reported that miR-423-5p expression was increased in gliomas and was a potential tumor promoter via targeting ING-4. The overexpression of miR-423-5p resulted in upregulation of important signaling molecules such as p-AKT and p-ERK1/2. In clinical samples, miR-423-5p was dysregulated, and a corresponding alteration in ING-4 expression was observed (P = .0207). Furthermore, the overexpression of miR-423-5p strengthened glioma cell proliferation, angiogenesis, and invasion. Finally, miR-423-5p overexpression also strengthened GBM neurosphere formation and rendered glioma cells resistant to temozolomide (TMZ). Conclusion This study establishes that miR-423-5p functions as an oncogene in glioma tissues by suppressing ING-4 and suggests that it has therapeutic potential for glioma.

BAP1 mutations in high-grade meningioma: implications for patient care.

Abstract: We have recently shown that the breast cancer (BRCA)1-associated protein-1 tumor suppressor gene (BAP1) is inactivated in a subset of clinically aggressive meningiomas that display rhabdoid histomorphology. Immunohistochemistry for BAP1 protein provides a rapid and inexpensive method for screening suspected cases. Notably, some patients with BAP1-mutant meningiomas have germline BAP1 mutations and BAP1 tumor predisposition syndrome (TPDS). It appears that nearly all patients with germline BAP1 mutations develop malignancies by age 55, most frequently uveal melanoma, cutaneous melanoma, pleural or peritoneal malignant mesothelioma, or renal cell carcinoma, although other cancers have also been associated with BAP1 TPDS. Therefore, when confronted with a patient with a potentially high-grade rhabdoid meningioma, it is important that neuropathologists assess the BAP1 status of the tumor and that the patient's family history of cancer is carefully ascertained. In the appropriate clinical setting, genetic counseling and germline BAP1 DNA sequencing should be performed. A cancer surveillance program for individuals who carry germline BAP1 mutations may help identify tumors such as uveal melanoma, cutaneous melanoma, and renal cell carcinoma at early and treatable stages. Because BAP1-mutant meningiomas are rare tumors, multi-institutional efforts will be needed to evaluate therapeutic strategies and to further define the clinicopathologic features of these tumors.

The radiosurgery fractionation quandary: single fraction or hypofractionation?

Abstract: Stereotactic radiosurgery (SRS), typically administered in a single session, is widely employed to safely, efficiently, and effectively treat small intracranial lesions. However, for large lesions or those in close proximity to critical structures, it can be difficult to obtain an acceptable balance of tumor control while avoiding damage to normal tissue when single-fraction SRS is utilized. Treating a lesion in 2 to 5 fractions of SRS (termed "hypofractionated SRS" [HF-SRS]) potentially provides the ability to treat a lesion with a total dose of radiation that provides both adequate tumor control and acceptable toxicity. Indeed, studies of HF-SRS in large brain metastases, vestibular schwannomas, meningiomas, and gliomas suggest that a superior balance of tumor control and toxicity is observed compared with single-fraction SRS. Nonetheless, a great deal of effort remains to understand radiobiologic mechanisms for HF-SRS driving the dose-volume response relationship for tumors and normal tissues and to utilize this fundamental knowledge and the results of clinic studies to optimize HF-SRS. In particular, the application of HF-SRS in the setting of immunomodulatory cancer therapies offers special challenges and opportunities.

Diagnostic challenges in meningioma

Abstract: Advances in molecular profiling and the application of advanced imaging techniques are currently refreshing diagnostic considerations in meningioma patients Not only technical refinements but also sophisticated histopathological and molecular studies have the potential to overcome some of the challenges during meningioma management Exact tumor delineation, assessment of tumor growth, and pathophysiological parameters were recently addressed by "advanced" MRI and PET In the field of neuropathology, high-throughput sequencing and DNA methylation analysis of meningioma tissue has greatly advanced the knowledge of molecular aberrations in meningioma patients These techniques allow for more reliable prediction of the biological behavior and clinical course of meningiomas and subsequently have the potential to guide individualized meningioma therapy However, higher costs and longer duration of full molecular work-up compared with histological assessment may delay the implementation into clinical routineThis review highlights the diagnostic challenges of meningiomas from both the neuroimaging as well as the neuropathological side and presents the latest scientific achievements and studies potentially helping in overcoming these challenges It complements the recently proposed European Association of Neuro-Oncology guidelines on treatment and diagnosis of meningiomas by integrating data on nonstandard imaging and molecular assessments most likely impacting the future

Seizure control as a new metric in assessing efficacy of tumor treatment in low-grade glioma trials.

Abstract: Patients with low-grade glioma frequently have brain tumor-related epilepsy, which is more common than in patients with high-grade glioma. Treatment for tumor-associated epilepsy usually comprises a combination of surgery, anti-epileptic drugs (AEDs), chemotherapy, and radiotherapy. Response to tumor-directed treatment is measured primarily by overall survival and progression-free survival. However, seizure frequency has been observed to respond to tumor-directed treatment with chemotherapy or radiotherapy. A review of the current literature regarding seizure assessment for low-grade glioma patients reveals a heterogeneous manner in which seizure response has been reported. There is a need for a systematic approach to seizure assessment and its influence on health-related quality-of-life outcomes in patients enrolled in low-grade glioma therapeutic trials. In view of the need to have an adjunctive metric of tumor response in these patients, a method of seizure assessment as a metric in brain tumor treatment trials is proposed.