Intracranial Malignancies Research Articles

The Short-Term and Intermediate-Term Risk of Second Neoplasms After Diagnosis and Treatment of Unilateral Vestibular Schwannoma: Analysis of 9460 Cases

To determine the incidence of second intracranial neoplasms after the diagnosis and treatment of sporadic vestibular schwannoma (VS). Analysis of the Surveillance, Epidemiology, and End Results (SEER) database including all patients identified with a diagnosis of VS and a second intracranial tumor. The Kaplan-Meier method was used to determine the incidence of second tumors while allowing for censoring at loss to follow-up or death. Multivariable associations between treatment modality and second tumor formation were explored using Cox proportional hazards regression analysis. Two illustrative cases are also presented. In all, 9460 patients with unilateral VS were identified between 2004 and 2012. Overall, 66 (0.7%) patients experienced a separate intracranial tumor, benign or malignant, after treatment of VS. Kaplan-Meier estimates for time to second neoplasm at 1, 3, and 5years were 0.3%, 0.7%, and 0.8%, respectively. Multivariable comparison between VS treatment modalities revealed that the risk of second tumor formation was similar between radiation and surgery (hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.36-1.51; P=.93) but greater for tumors managed with observation alone compared with radiation (HR 2.48; 95% CI 1.31-4.71; P<.01). A total of 6 (0.06%) intracranial malignancies were diagnosed after VS treatment. Kaplan-Meier estimates for time to malignancy at 1, 3, and 5years were 0%, 0.1%, and 0.1%, respectively. After adjustment for age at diagnosis, sex, and treatment modality, the probability of malignancy after radiation was not greater than after observation alone or microsurgery (HR 4.88; 95% CI 0.85-28.14; P=.08) during the study period. The risk for the development of a second intracranial neoplasm, benign or malignant, at 5years after treatment of unilateral VS is approximately 0.8%, whereas the risk of acquiring a separate malignancy is 0.1%, or approximately 1 per 1000 cases. The short-term and intermediate-term incidence of second neoplasm after radiation of VS is not greater than the incidence after microsurgery or observation.

Pilot Preclinical and Clinical Evaluation of (4S)-4-(3-[18F]Fluoropropyl)-L-Glutamate (18F-FSPG) for PET/CT Imaging of Intracranial Malignancies.

Purpose(S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid (18F-FSPG) is a novel radiopharmaceutical for Positron Emission Tomography (PET) imaging. It is a glutamate analogue that can be used to measure xC- transporter activity. This study was performed to assess the feasibility of 18F-FSPG for imaging orthotopic brain tumors in small animals and the translation of this approach in human subjects with intracranial malignancies.Experimental DesignFor the small animal study, GS9L glioblastoma cells were implanted into brains of Fischer rats and studied with 18F-FSPG, the 18F-labeled glucose derivative 18F-FDG and with the 18F-labeled amino acid derivative 18F-FET. For the human study, five subjects with either primary or metastatic brain cancer were recruited (mean age 50.4 years). After injection of 300 MBq of 18F-FSPG, 3 whole-body PET/Computed Tomography (CT) scans were obtained and safety parameters were measured. The three subjects with brain metastases also had an 18F-FDG PET/CT scan. Quantitative and qualitative comparison of the scans was performed to assess kinetics, biodistribution, and relative efficacy of the tracers.ResultsIn the small animals, the orthotopic brain tumors were visualized well with 18F-FSPG. The high tumor uptake of 18F-FSPG in the GS9L model and the absence of background signal led to good tumor visualization with high contrast (tumor/brain ratio: 32.7). 18F-FDG and 18F-FET showed T/B ratios of 1.7 and 2.8, respectively. In the human pilot study, 18F-FSPG was well tolerated and there was similar distribution in all patients. All malignant lesions were positive with 18F-FSPG except for one low-grade primary brain tumor. In the 18F-FSPG-PET-positive tumors a similar T/B ratio was observed as in the animal model.Conclusions18F-FSPG is a novel PET radiopharmaceutical that demonstrates good uptake in both small animal and human studies of intracranial malignancies. Future studies on larger numbers of subjects and a wider array of brain tumors are planned.Trial RegistrationClinicalTrials.gov NCT01186601

The Rationale for Targeted Therapies and Stereotactic Radiosurgery in the Treatment of Brain Metastases.

Brain metastases are the most common intracranial malignancy. Many approaches, including radiation therapy, surgery, and cytotoxic chemotherapy, have been used to treat patients with brain metastases depending on the patient's disease burden and symptoms. However, stereotactic surgery (SRS) has revolutionized local treatment of brain metastases. Likewise, targeted therapies, including small-molecule inhibitors and monoclonal antibodies that target cancer cell metabolism or angiogenesis, have transformed managing systemic disease. Prospective data on combining these treatments for synergistic effect are limited, but early data show favorable safety and efficacy profiles. The combination of SRS and targeted therapy will further individualize treatment, potentially obviating the need for cytotoxic chemotherapy or whole-brain radiation. There is a great need to pursue research into these exciting modalities and novel combinations to further improve the treatment of patients with brain metastases. This article discusses reported and ongoing clinical trials assessing the safety and efficacy of targeted therapy during SRS. Treatment of patients with brain metastases requires a multidisciplinary approach. Stereotactic radiosurgery is increasingly used in the upfront setting to treat new brain metastasis. Targeted therapies have revolutionized systemic treatment of many malignancies and may sometimes be used as initial treatment in metastatic patients. There is sparse literature regarding safety and efficacy of combining these two treatment modalities. This article summarizes the supporting literature and highlights ongoing clinical trials in combining radiosurgery with targeted therapy.

ATNT-21PRECLINICAL AND INITIAL PHASE 1 EXPERIENCE FOR USE OF MEBENDAZOLE AS UP FRONT THERAPY FOR HIGH GRADE GLIOMA

INTRODUCTION: Identifying drugs that can reach brain cancers in effective concentrations has been a serious challenge. There has been a body of evidence implicating anti-cancer mechanisms and utility for antihelminthics benzimidazoles, and preclinical and clinical development of repurposed mebendazole is gaining momentum. Mebendazole has been used safely as an anti-parasitic drug, and in high doses, in humans starting in 1972. METHODS: Multiple intracranial models of glioblastoma and medulloblastoma have been used for efficacy studies on intracranial tumors. Studies with orally administered mebendazole demonstrate favorable pharmacokinetics with 70 to 80% of mebendazole serum levels measured in the in the mouse brain and brain tumors. RESULTS: Our laboratory serendipitously identified benzimidazole anti-cancer activity in brain cancers and found that of the approved benzimidazoles, mebendazole showed the best survival benefit. We observe in preclinical testing it reaches effective concentrations in intracranial tumors, acts to prevent tubulin polymerization, has an additional anti-VEGR2 and anti-angiogenesis mechanisms and significantly improves survival in a variety of intracranial malignancy models. We have translated our preclinical findings into a Phase I trial, using mebendazole for upfront therapy, concurrent with temozolomide therapy for newly diagnosed patients with a high grade glioma. We have further improved mebendazole with drug combinations. CONCLUSION: The preclinical and phase 1 clinical findings are consistent with safe and possibly effective use of an improved formulation of oral mebendazole. We provide evidence that continued optimization of mebendazole based oral therapy and planning of future clinical trials may yield an additional tool for therapy of GBM and other intracranial tumors.

A Feasibility Study of a Tilted Head Position in Helical Tomotherapy for Fractionated Stereotactic Radiotherapy of Intracranial Malignancies.

Herein, we evaluated the feasibility of placing patients in a tilted head position as part of routine clinical practice for fractionated stereotactic radiotherapy (FSRT) of intracranial tumors using helical tomotherapy (HT), by assessing its dosimetric benefit and setup accuracy. We reviewed treatment plans of four cases that were to receive FSRT for brain lesions in normal and head-tilted positions. These patients underwent two computed tomography (CT) scans: first in the normal supine position and then in the supine position with the head tilted at a 458 angle. Two separate HT plans for each position were generated in these four patients, using the same planning parameters. Plans were compared for target conformity and dose homogeneity. Maximum and average doses to critical organs, including normal brain, brain stem, optic chiasm, optic nerves, and the eyes, were considered. To evaluate setup accuracy, patient movement during treatment was assessed by post-treatment megavoltage CT scans. Both HT plans achieved similar conformal and homogeneous dose coverage to the target. Head-tilted HT delivered lower average and maximum doses to critical organs in the cases where the tumor was located on the same plane with critical organs, particularly when they were not directly attached. Placement in the head-tilted position without a mouthpiece allowed for increased patient movement during treatment, while use of a mouthpiece reduced patient movement to even less than that observed for normal setup in the supine position. This pilot study showed that placement in a tilted head position for FSRT of intracranial tumors using HT may be of clinical use, but depends on the tumor location.

The Dynamics of Interactions Among Immune and Glioblastoma Cells.

Glioblastoma is the most common intracranial malignancy that constitutes about 50 % of all gliomas. Despite aggressive, multimodal therapy consisting of surgery, radiation, and chemotherapy, the outcome of patients with glioblastoma remains poor with 5-year survival rates of <10 %. Resistance to conventional therapies is most likely caused by several factors. Alterations in the functions of local immune mediators may represent a critical contributor to this resistance. The tumor microenvironment contains innate and adaptive immune cells in addition to the cancer cells and their surrounding stroma. These various cells communicate with each other by means of direct cell-cell contact or by soluble factors including cytokines and chemokines, and act in autocrine and paracrine manners to modulate tumor growth. There are dynamic interactions among the local immune elements and the tumor cells, where primarily the protective immune cells attempt to overcome the malignant cells. However, by developing somatic mutations and epigenetic modifications, the glioblastoma tumor cells acquire the capability of counteracting the local immune responses, and even exploit the immune cells and products for their own growth benefits. In this review, we survey those immune mechanisms that likely contribute to glioblastoma pathogenesis and may serve as a basis for novel treatment strategies.

Differentiating high and low grade pediatric brain tumors using diffusional kurtosis imaging

The purpose of this study is to determine the accuracy with which a non-Gaussian measure of diffusion, mean kurtosis (MK), predicts the histologic grade of pediatric brain tumors. After institutional review board approval, 21 World Health Organization (WHO) grade I, 7 WHO grade II, and 7 WHO grade IV pathologically-proven intracranial pediatric malignancies were retrospectively reviewed for preoperative diffusional kurtosis imaging. Multiple diffusion metrics of the tumors including MK, mean diffusivity (MD) and fractional anisotropy (FA) were determined. Comparisons between groups were performed using the Mann-Whitney test (p < .05). Receiver operating characteristics analysis was done to assess accuracy of each metric in predicting histologic grade. MK was significantly higher for grade IV neoplasms (0.97, p < 0.0004) than grade I (0.62) or grade II (0.67) tumors. MD was significantly higher for grade I (1.43) compared with grade IV neoplasms (1.07, p < 0.018), however not for grade II (1.43) compared with grade IV (p < 0.08) tumors. FA did not differ significantly between grades. Area under the recei- ver operating characteristic curve was highest for MK (0.94) and lower for MD (0.89). FA performed only slightly better than chance (0.54). MK is an accurate diffusion metric for predicting histologic grade of pediatric brain tumors, consistent with conclusions from prior studies demonstrating similar results in adult populations.

Implementation and validation of a new fixation system for stereotactic radiation therapy: An analysis of patient immobilization

PurposeStereotactic radiation therapy is an established treatment technique for intracranial malignancies. We evaluated a new intracranial immobilization system with an emphasis on determining the intrafraction motion and the correlation of this motion with treatment time. Methods and materialsPatients were immobilized using the trUpoint ARCH fixation system (CIVCO Medical Solutions). We collected data from 85 lesions in 73 patients treated between November 2011 and December 2013. Sixty-nine of 73 patients (95%) used the complete mask system; for the remaining 4 patients, the system had to be adapted. Patients were treated using volumetric modulated arc therapy stereotactic radiation therapy on a TrueBeam linear accelerator (Varian Medical Systems, Palo Alto, CA). Fraction doses of 2-8 Gy were applied in 4-30 fractions. Daily cone beam computed tomography imaging was performed before the treatment and was matched to the reference computed tomography using a 6-degrees-of-freedom automatching procedure. Additionally, posttreatment cone beam computed tomography scans were performed to assess intrafraction motion for 67 patients (375 fractions). ResultsThe average 3-dimensional setup error was 2.1 ± 2.9 mm. The mean pitch and roll was −0.1 ± 0.7° and 0.2 ± 0.7°. A total of 98.0% of the pitch values and 98.9% of the roll values were <1.5°. Mean intrafractional motion was 0.51 mm (±0.27) and mean treatment time was 10.1 minutes (±1.4). The maximum intrafractional motion was 2.0 mm in the longitudinal direction; 95% of the total shifts were <1.4 mm. The linear regression showed a weak but significant influence (R2 = 0.26, P = .01) of the treatment time on the total intrafractional shift. ConclusionsThe new intracranial immobilization system appears to be robust in terms of setup accuracy, intrafraction motion, and repositioning of the mask system.

The controversy surrounding the use of whole-brain radiotherapy in brain metastases patients.

Brain metastases account for the majorityof intracranial malignancies and carry an extremely high mortality and, anecdotes aside, are associated with very short survival times. With improvements in treatment including surgery, systemic therapy, and radiotherapy, a tiny minority of patients are living longer. Unfortunately, for an unselected population of patients with brain metastases representing the vast majority of these patients, median survival is still measured in months rather than years. It is well recognized that the therapies and the disease itself can have a significant impact on a patient’s cognition and quality of life, even in this short survival duration. One of the more debilitating side effects associated with brain metastases is cognitive decline, most notably affecting memory. The underlying pathology of cognitive decline in patients with brain metastases is multifactorial. A common cause is the cancer itself and, of course, the occurrence of brain metastases. Medications associated with symptomatic management of the consequences from brain metastases, systemic chemotherapeutic agents, and whole-brain radiotherapy (WBRT) are contributing factors. Additionally, comorbid factors such as anxiety, fatigue, depression, and direct involvement of memory centers in the brain can contribute to memory decline. Various techniques have been and are being developed to prevent or treat neurocognitive decline in brain cancer patients. 1 WBRT has been integral in the treatment of brain metastases for well over half a century. For example, Chao et al demonstrated symptomatic improvement in 63% of patients treated with this approach. 2 Improvements insurgical and radiosurgicaltechniques have increasingly led to applying WBRT as an adjuvant treatment following resection or radiosurgery (SRS) to improve local, leptomeningeal, and regional control. 3‐7 Over the last decade, an increasing trend has emerged toward utilizing SRS alone for patients with multiple brain metastases and reserving WBRTas a treatment of last resort for salvage of widespread intracranial metastatic disease. In this review, we will scrutinize the evidence suggesting that WBRT can be abandoned in a significant majority of patients, and we posit that this is in fact a dangerous trend that is not adequately supported by the evidence at hand. Further, wewill highlight the significant advances in modulating WBRT-associated cognitive deficits, which would be expected to further improve the therapeutic window associated with this modality.

Molecular and Genetic Predictors of Breast-to-Brain Metastasis: Review and Case Presentation.

Brain metastases are the most common intracranial malignancy, and breast cancer is the second most common cancer to metastasize to the brain. Intracranial disease is a late manifestation of breast cancer with few effective treatment options, affecting 15-50% of breast cancer patients, depending upon molecular subtype. In this review article, we describe the genetic, molecular, and metabolic changes in breast cancer cells that facilitate breast to brain metastasis. We believe that advances in the understanding of breast to brain metastasis pathogenesis will lead to targeted molecular therapies and to improvements in the ability to prospectively identify patients at increased risk for developing intracranial disease.

Down Regulated Expression of Claudin-1 and Claudin-5 and Up Regulation of &amp;#946;-Catenin: Association with Human Glioma Progression

Glioblastoma multiforme is the most common form of intracranial malignancy in humans, and is characterized by aggressive tumor growth, tissue invasion and neurodegenerative properties. The present study investigated the expression status of tight junction associated Claudin 1 (CLDN1), Claudin 5 (CLDN5) and Adheren junction associated β-catenin genes in the light of their critical role in the progression of both low- and high-grade human gliomas. Using quantitative PCR and Western blot methods the mRNA and protein status of CLDN1, CLDN5 and β-catenin genes were studied in a total of 25 human gliomas of World Health Organization (WHO) grades I-IV, non-cancerous control brain tissues and their corresponding model cell lines (C6, U373, U118, T98 and U87MG). Quantitative analysis of the transcript and protein expression data showed that CLDN1 and CLDN5 were significantly down regulated (p=<0.001) in tumors of all four grades and model cell lines. This decrease in expression pattern was in accordance with the increasing grade of the tumor. A 4-fold stronger reduction of CLDN1 when compared to CLDN5 was evident in high-grade tumors. Interestingly, β-catenin was up regulated in all tumor types we studied (p=<0.005). Our findings, suggest that down regulated CLDN1 and CLDN5 genes have potential relevance in relation to the progression of glioblastoma multiforme. Hence, their therapeutic targeting may provide both insight and leads to control the cellular proliferation and subsequent invasiveness among affected individuals.

NT-32 * TISSUE ABLATION DYNAMICS DURING MAGNETIC RESONANCE-GUIDED LASER INDUCED THERMAL THERAPY FOR INTRACRANIAL TUMORS

BACKGROUND: Magnetic Resonance-guided Laser Induced Thermal Therapy (MRgLITT) is a minimally-invasive procedure used in the treatment of intracranial tumors, epilepsy and pain. Thermal damage is estimated using real-time MR thermometry but little is known about the dynamics of the process and how various intracranial tumors affect overall ablation. OBJECTIVES: Determine the relationship between thermal energy delivery and the time to maximal estimated thermal damage in the setting of previously untreated glioblastoma multiforme (GBM), recurrent GBM, and metastatic tumors or radiation necrosis. We aim to understand whether differences exist between these intracranial malignancies and how the ablation process is affected. METHODS: We used real-time ablation data from 24 patients across five unique intracranial pathologies. Ablations were performed using the Visualase Thermal Therapy System (Visulase Inc.) using a 980-nm diffusing tip diode laser. Thermal damage area was plotted against time for each ablation. Subsequently, the duration required to reach 50% (t50) and 97% (t97) of maximum damage was estimated. Comparisons were then made between different intracranial pathologies. RESULTS: The average (mean ± SEM) t97 for previously untreated GBM (n = 7) recurrent GBM (n = 6) and tumor metastasis/radiation necrosis (n = 7) are 167 ± 18, 165 ± 22, 97 ± 22 seconds, respectively. The mean t97 is significantly shorter for tumor metastasis/radiation necrosis when compared with previously untreated GBM (p < 0.05). CONCLUSIONS: While optimal duration of thermal ablation varies between intracranial tumors, we found that metastatic tumor/radiation necrosis requires significantly shorter duration of ablation. In most cases, maximal ablation was reached long before the industry recommended ablation time. Understanding the duration required to reach maximal ablation may reduce thermal exposure times during the ablation process. Future studies are needed to examine the relationship between ablation power, irrigation speed, and the effect of prior therapies on the ablation dynamics.

Expression and prognostic significance of TCTN1 in human glioblastoma.

BackgroundGlioblastoma (GBM) is the most common and lethal intracranial malignancy in adults, with dismal prognosis despite multimodal therapies. Tectonic family member 1 (TCTN1) is a protein involved in a diverse range of developmental processes, yet its functions in GBM remain unclear. This study aims to investigate expression profile, prognostic value and effects of TCTN1 gene in GBM.MethodsProtein levels of TCTN1 were assessed by immunohistochemical staining using a tissue microarray constructed by a Chinese cohort of GBM patients (n = 110), and its mRNA expression was also detected in a subset of this cohort. Kaplan-Meier analysis and Cox regression were performed to estimate the prognostic significance of TCTN1. Similar analyses were also conducted in another two independent cohorts: The Cancer Genome Atlas (TCGA) cohort (n = 528) and the Repository for Molecular Brain Neoplasia Data (REMBRANDT) cohort (n = 228). For the TCGA cohort, the relationships between TCTN1 expression, clinical outcome, molecular subtypes and genetic alterations were also analysed. Furthermore, proliferation of TCTN1 overexpressed or silenced GBM cells was determined by CCK-8 assays.ResultsAs discovered in three independent cohorts, both mRNA and protein levels of TCTN1 expression were markedly elevated in human GBMs, and higher TCTN1 expression served as an independent prognostic factor predicting poorer prognosis of GBM patients. Additionally, in the TCGA cohort, TCTN1 expression was dramatically decreased in patients within the proneural subtype compared to other subtypes, and significantly influenced by the status of several genetic aberrations such as CDKN2A/B deletion, EGFR amplification, PTEN deletion and TP53 mutation. The prognostic value of TCTN1 was more pronounced in proneural and mesenchymal subtypes, and was also affected by several genetic alterations particularly PTEN deletion. Furthermore, overexpression of TCTN1 significantly promoted proliferation of GBM cells, while its depletion evidently hampered cell growth.ConclusionsTCTN1 is elevated in human GBMs and predicts poor clinical outcome for GBM patients, which is associated with molecular subtypes and genetic features of GBMs. Additionally, TCTN1 expression impacts GBM cell proliferation. Our results suggest for the first time that TCTN1 may serve as a novel prognostic factor and a potential therapeutic target for GBM.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-014-0288-9) contains supplementary material, which is available to authorized users.

Abstract 1183: Establishment,characterization and utilization of models of central nervous system metastasis

Abstract Metastases to the central nervous system (CNS) are the most common intracranial malignancy and are typically associated with survival times of only a few months. Lung and breast are the most common type of CNS metastasis, representing over half of such tumors. The molecular characteristics of these tumors as well as the factors driving cancers to metastasize to the CNS are poorly understood. This is due in part to inaccessibility of clinical samples and a lack of established, well-characterized models. In order to shed light on the molecular biology of these highly heterogeneous tumors and establish resources for preclinical testing, we are working to create both in vivo and in vitro models of CNS metastases originating from lung or breast cancer. We have thus far received surgical specimens from 7 lung and two breast CNS metastases. Of these, one was a spine metastasis and 6 were brain metastases. Each surgical specimen was used for the generation of patient-derived xenografts (PDX) and cell lines. Of these specimens, we have successfully established continuous cell lines of CNS metastases originating from three lung adenocarcinomas, one squamous lung carcinoma and one ductal breast carcinoma. To verify the presence of metastatic carcinoma cells in culture, cell lines were characterized by immunofluorescence based on staining profiles obtained from each tumor's pathology report. Adenocarcinomas of the lung expressed cytokeratins typical of lung cancer (CK7, 8 and 18), as well as Napsin-A, a highly specific pulmonary marker. The squamous cell carcinoma of the lung expressed these as well as CK5/6 and p63-α, pathological markers of squamous differentiation. A metastatic ductal carcinoma of the breast expressed ER, Her2, GATA-3, and Vimentin. For the development of PDX models, tumors were initially implanted into flank of NOG mice and then passaged orthotopically for preclinical testing. Of nine implants, tumor growth was evident for 3 animals harboring adenocarcinoma of the lung, 2 with squamous cell carcinoma of the lung, and 1 with breast carcinoma. Samples from metastatic tissue, xenograft tissue and primary tumors (when available) were flow sorted to identify different clonal subpopulations and sequenced for exome and RNA level changes. Genomic characterization of the different clones allowed reconstruction of the evolution of metastasis and identified therapeutically targetable genes. Studies are ongoing to develop personalized preclinical mouse studies based on the integration of multi-omics data derived from the models and patient tumors. Citation Format: Kyle N. Johnson, Paul M. Gonzalez, Mario Sepulveda, Loren Gorgol, Jennifer Glen, Danielle M. DiPerna, Mark Bernstein, Steven A. Toms, Bodour Salhia. Establishment,characterization and utilization of models of central nervous system metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1183. doi:10.1158/1538-7445.AM2014-1183

Molecular heterogeneity of glioblastoma and its clinical relevance.

Glioblastoma is the most common intracranial malignancy and constitutes about 50 % of all gliomas. Both inter-tumor and intra-tumor histological heterogeneity had been recognized by the early 1980-ies. Recent works using novel molecular platforms provided molecular definitions of these tumors. Based on comprehensive genomic sequence analyses, The Cancer Genome Atlas Research Network (TCGA) cataloged somatic mutations and recurrent copy number alterations in glioblastoma. Robust transcriptome and epigenome studies also revealed inter-tumor heterogeneity. Integration and cluster analyses of multi-dimensional genomic data lead to a new classification of glioblastoma tumors into subtypes with distinct biological features and clinical correlates. However, multiple observations also revealed tumor area-specific patterns of genomic imbalance. In addition, genetic alterations have been identified that were common to all areas analyzed and other alterations that were area specific. Analyses of intra-tumor transcriptome variations revealed that in more than half of the examined cases, fragments from the same tumor mass could be classified into at least two different glioblastoma molecular subgroups. Intra-tumor heterogeneity of molecular genetic profiles in glioblastoma may explain the difficulties encountered in the validation of oncologic biomarkers, and contribute to a biased selection of patients for single target therapies, treatment failure or drug resistance. In this paper, we summarize the currently available literature concerning inter- and intra-tumor molecular heterogeneity of glioblastomas, and call attention to the importance of this topic in relation to the growing efforts in routine molecular diagnostics and personalized therapy.

Cytologic characterization of atypical teratoid/rhabdoid tumor in cerebrospinal fluid.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare and highly aggressive intracranial malignancy with a predilection to spread along the cerebrospinal fluid (CSF) pathways. To the authors' knowledge, the cytopathologic characteristics of this tumor have not been extensively studied in CSF. Herein the authors report CSF cytomorphology from a series of patients with histologically documented AT/RT. A retrospective review of 40 malignant CSF specimens from 10 patients with histologically confirmed AT/RT was conducted. All the patients were female and ranged in age from 0.8 to 19.6 years at the time of the initial diagnosis (median age, 1.3 years). Cytospin preparations were reviewed. In the majority of cases, at least 2 slides were prepared with the Wright-Giemsa and/or Papanicolaou stains. The CSF samples were predominantly moderately to highly cellular (80%). The 3 most common features were eccentrically placed nuclei (72.5%), prominent nucleoli (70%), and large tumor cells (67.5%). Two principal malignant cell types were noted; the most striking and recognizable form was a large, usually rhabdoid cell with an eccentrically placed nucleus, prominent nucleolus, and abundant cytoplasm, which was observed in 47.5% of the cases. The second type had a small cell appearance and was noted in 57.5% of the cases. Both large rhabdoid and small malignant cells were reported in 25% of the cases. A significant percentage of CSF AT/RT cases consist of only the small cell component, without the characteristic large rhabdoid cells. Familiarity with this pattern of spread is imperative in differentiating AT/RT from other small cell malignancies such as medulloblastoma, because the clinical behavior and therapeutic regimens differ.

Renal cell carcinoma to haemangioblastoma metastasis: A rare manifestation of Von Hippel–Lindau syndrome

Brain metastases are the most common intracranial malignancy in adults and may occasionally deposit within a pre-existing primary brain neoplasm. We describe, in two directly related family members, the rare occurrence of renal cell carcinoma (RCC) metastasis to haemangioblastoma (HB) in the context of Von Hippel–Lindau syndrome. Detection of this phenomenon can be marred by histological overlap between RCC and HB and therefore careful histological examination, and consideration of supportive immunohistochemistry, is required when examining all HB resections. Metastatic RCC to HB upstages a primary RCC and is clinically diagnostic of Von Hippel–Lindau syndrome.

Anticoagulation for noncardiac indications in neurologic patients: comparative use of non-vitamin k oral anticoagulants, low-molecular-weight heparins, and warfarin.

Patients with neurologic disorders may develop a wide variety of thromboembolic events, both as a primary manifestation and as a consequence of their underlying neurologic condition. There are many available options for anticoagulation, ranging from warfarin to the parenteral subcutaneously administered anticoagulants to the non-vitamin K oral anticoagulants (NOACs). Warfarin is orally available, well-studied, and easily reversible in the setting of bleeding, but has a prolonged onset of action, measured in days, and equally slow offset; requires frequent monitoring for dose titration; and has multiple drug-drug and food-drug interactions. Parenteral heparin-based anticoagulants are well-studied and have more predictable pharmacokinetics but are often more expensive, only partially reversible, and require daily injections, which can be difficult for patients to tolerate over long periods of time. The NOACs are easy to administer and have predictable pharmacokinetics but are expensive, not easily reversible, and are not as extensively studied. Specific agents are preferable in some defined neurologic conditions. For acute ischemic stroke, we do not recommend immediate anticoagulation with any agent. For patients with intracranial malignancy (either primary or metastatic), we recommend a low-molecular-weight heparin (LMWH) rather than warfarin or a NOAC. For thromboembolic disease in the setting of spinal cord injury, warfarin, LMWH, or the NOACs are reasonable options. In the setting of VTE or stroke related to antiphospholipid antibody syndrome (APS), we recommend long-term warfarin anticoagulation with an INR goal of 2-3, pending the results of ongoing research involving the NOACs. For cerebral venous sinus thrombosis not related to malignancy or APS, we recommend the use of LMWH in the acute setting, followed by at least three months of warfarin. In this article, we discuss the pharmacology, pathophysiology, and comparative research that served as a basis for our recommendations.

SU‐E‐QI‐12: Morphometry Based Measurements of the Structural Response to Whole Brain Radiation

Purpose:Although state of the art radiation therapy techniques for treating intracranial malignancies have eliminated acute brain injury, cognitive impairment occurs in 50–90% of patients who survive &gt;6mo post irradiation. Quantitative characterization of therapy response is needed to facilitate therapeutic strategies to minimize radiation induced cognitive impairment [1]. Deformation based morphometry techniques [2, 3] are presented as a quantitative imaging biomarker of therapy response in patients receiving whole brain radiation for treating medulloblastoma.Methods:Post‐irradiation magnetic resonance imaging (MRI) data sets were retrospectively analyzed in N=15 patients, &gt;60 MR image datasets. As seen in Fig 1(a), volume changes at multiple time points post‐irradiation were quantitatively measured in the cerebrum and ventricles with respect to pre‐irradiation MRI. A high resolution image Template, was registered to the pre‐irradiation MRI of each patient to create a brain atlas for the cerebrum, cerebellum, and ventricles. Skull stripped images for each patient were registered to the initial pre‐treatment scan. Average volume changes in the labeled regions were measured using the determinant of the displacement field Jacobian.Results:Longitudinal measurements, Fig 1(b‐c), show a negative correlation p=.06, of the cerebral volume change with the time interval from irradiation. A corresponding positive correlation, p=.01, between ventricular volume change and time interval from irradiation is seen. One sample t‐test for correlations were computed using a Spearman method. An average decrease in cerebral volume, p=.08, and increase in ventricular volume, p&lt;.001, was observed. The radiation dose was seen directly proportional to the induced volume changes in the cerebrum, r=−.44, p&lt;.001, Fig 1(d).Conclusion:Results indicate that morphometric monitoring of brain tissue volume changes may potentially be used to quantitatively assess toxicity and response to radiation and may provide insight in developing new therapeutic approaches and monitoring efficacy.

Higher mortality rates among the elderly with mild traumatic brain injury: a nationwide cohort study

BackgroundIt is known that the risk of death in elderly patients with moderate to severe traumatic brain injury is increased. However, the relationship between mild traumatic brain injury and death has never been established. We investigated the mortality rates of older patients with mild traumatic brain injury in Taiwan to evaluate if there is a higher risk of death compared with the general population.MethodsWe utilized a sampled National Health Insurance claims database containing one million beneficiaries. We followed all adult beneficiaries older than 65 years from January 1, 2005 till December 31, 2009 to see if they died. We further identified patients with mild traumatic brain injury and compared their risk of death with the general population.ResultsWe identified 5997 patients with mild traumatic brain injury and 84,117 patients without mild traumatic brain injury. After controlling for age, gender, urbanization level, socioeconomic status, diabetes, hypertension, history of alcohol intoxication, history of ischemic stroke, history of intracranial hemorrhage, malignancies, dementia and Charlson Comorbidity Index score, the adjusted hazard ratio was 1.25 (95% confidence interval, 1.16—1.34).ConclusionsMild traumatic brain injury is an independent significant risk factor for death in the elderly.