High-grade Primary Brain Tumors Research Articles

The Role of Transforming Growth Factor Beta and Smad Receptors in Determining Prognosis in High-Grade Primary Brain Tumors: Glioblastoma Multiforme

Abstract Introduction High-grade primary brain tumors cause serious morbidity and mortality. This study aimed to investigate the role of transforming growth factor beta (TGF-β) and suppressor of mothers against decapentaplegic (Smad) receptors in high-grade primary brain tumors. Material and Method Thirteen patients with a pathological diagnosis of glioblastoma multiforme were included in the study. Pathological preparations of each patient were analyzed retrospectively in histochemistry and immunohistochemistry laboratories. Transforming growth factor beta 1, TGF-β2, TGF-β3, Smad 1/2/3, Smad 6, and Smad 7 stainings were evaluated, and the immunoreactivity densities were examined. Result We found out an increase in the expression of TGF-β1 and TGF-β3 protein. Regarding the inhibitin receptors, Smad 6 showed much more expression than Smad 7. Thus, we found that Smad 6 has a protective effect and role in the tissue. Immunhistochemically, TGF-β family stains, which are activated by types I-and -II receptors, and the stainless staining of the Smad family might also be showing that the TGF-β family is taking action with a secondary pathway other than the Smad family. Conclusion In addition to Smad family receptors, Shc-GBR2, SARA, and Ras-Erk1/2 receptors should be investigated in future research. After that, the prognosis, diagnosis, and patient-based chemotherapy strategies for the treatment of glioblastoma multiforme may take a more prominent role.

OL92 - Radiomics features of 11[C]-MET PET/CT in primary brain tumors: preliminary results on grading discrimination using a machine learning model

1096 Background: Nowadays Artificial Intelligence (AI) algorithms have demonstrated remarkable progress in image-recognition tasks and could be useful for the new concept of precision medicine in order to help physicians in the choice of therapeutic strategies for brain tumors. Previous data suggest that, in primary brain tumor, amino acid PET may demarcate more accurately the active disease than paramagnetic enhanced MRI that is the standard method of the evaluation in brain tumors and help in the evaluation of disease grading, as a fundamental basis for the correct clinical management of these patients. The aim of this study is to propose a radiomics workflow in order to create a predictive model on 11[C]-MET PET/CT scan images capable to discriminate between low-grade and high-grade primary brain tumors. Materials and Methods: in this retrospective study we selected fifty-six patients affected by primary brain tumor who underwent 11[C]-MET PET/CT from January 2016 to December 2019 at the Nuclear Medicine department of the Cannizzaro Hospital of Catania. Histological specimen the analysis was available in all patients in order to confirm the diagnosis and grading disease. PET/CT acquisition was performed after 10 minutes from the administration of 11C-Methionine (401-610 MBq) for a time acquisition of 15 minutes. 11[C]-MET PET/CT images were acquired using two scanners (24 patients on a Siemens scan and 32 patients on a GE scan). Then, LIFEx software was used to perform the segmentation and the extraction of features in order to identify the volume of interest (VOI) and to extract features of first, second, and third-order. LIFEx calculates 44 RF reflecting the VOI shape, the VOI voxel values, the histogram of VOI values, or the VOI textural content. A novel mixed descriptive-inferential sequential approach was used to identify a subset of relevant features that correlate with the outcome. A machine learning model based on discriminant analysis was tested in the evaluation of grading prediction (low vs high-grade) of 11[C]-MET PET/CT. Results: The machine learning model applicated in this study to stratify brain tumors as “low” and “high” grade showed discriminant texture features as follow: two features in fixed ROI respectively NGLDM Busyness (p-value: 0.1615) and GLZLM LZLGE (p-value 0.3207); three features in total volume respectively SHAPE Sphericity (p-value 0.0314), SHAPE Compacity (p-value 0.0215) and HISTO Kurtosis (p-value 0.0232). The results of performances, using a semi-automatic and user-independent segmentation process and an innovative feature extraction process on fixed ROI, showed a good performance in prediction of disease grade with an accuracy of 70.31% (AUC 64.13%) in all patients, of 80.51% (AUC 65.73%) in GE tomograph, of 84.98%(AUC 78.91%) in Siemens Tomograph. Using our model of machine learning with discriminant analysis the results of the performances were suboptimal in all patients group( 24 Siemens plus 32 GE) with an accuracy of 57.25 % and AUC of 58.51%. However in subgroup analysis, despite the low number of patients and different scanner, our model demonstrated good performances in the prediction of disease grade as follow: GE Scanner Accuracy 71.64 and AUC 62.8%; Siemens Scanner Accuracy 72,88% and AUC 78.91%. Conclusions: This preliminary study on radiomics features analysis of 11[C]-MET PET/CT suggests a possible value of Artificial Intelligence to assess primary brain tumors and to predict disease outcome in terms of grading discrimination at diagnosis. Further studies are needed to improve radiomics algorithms to personalize predictive and prognostic models and potentially support the medical decision process.

RTHP-32. FIRST EXPERIENCE WITH GAMMATILE PERMANENT IMPLANTS FOR RECURRENT BRAIN TUMORS

Abstract GammatileTM permanent brachytherapy implants have been FDA cleared for patients with recurrent brain tumors. We report our experience with the first 6 patients with recurrent high grade primary brain tumors treated with re-resection and implantation. Each tile contains 4 encapsulated radioactive Cs-131 seeds embedded in collagen. To determine the number of tiles needed, the potential tumor cavity surface area was estimated using the preoperative MRI images. The anticipated cavity surface area was calculated, the surface area of anticipated surgical approach was subtracted. This area was divided by 40mm2 (tile area) and this number of tiles were ordered. At the time of surgery, after maximal safe tumor resection, tiles were placed into the resection cavity and the surgical cavity closed as usual. On post-implant day 1, CT and MRI scans were performed. The cavity was contoured, then expanded by 5mm to create HRCTV. T1 MRI enhanced lesions were contoured as residual GTV (GTVr). A dose of 60Gy over the course of treatment was prescribed to HRCTV. In each of these 6 cases, over 95% of the HRCTV was covered by the 60Gy isodose surface, and GTVr D90 ranged from 22.9Gy to 113.8Gy. The additional time required for the tile placement in all cases was less than 10 minutes. Post-operatively exposure rates at 1m were less than 6 mR/hr (ranging from 1.3 to 3.2mR/h). Permanent GammaTile for recurrent brain tumors is a viable option for selected previously irradiated patients who are operative candidates. Benefits include irradiation of the tumor bed starting immediately after resection with no need to wait for wound healing, and no need to subsequently surgically remove the tile. We were able to accurately predict the number of tiles needed, although in one case collagen spacers were utilized. Due to low exposure rates, radiation protection issues are very manageable.

124I]CLR1404 PET/CT in High-Grade Primary and Metastatic Brain Tumors.

There is a continuous search for imaging techniques with high sensitivity and specificity for brain tumors. Positron emission tomography (PET) imaging has shown promise, though many PET agents either have a low tumor specificity or impractical physical half-lives. [124I]CLR1404 is a small molecule alkylphosphocholine analogue that is thought to bind to plasma membrane lipid rafts and has shown high tumor-to-background ratios (TBR) in a previous pilot study in brain tumor patients. This study attempts to define the clinical value of [124I]CLR1404 PET/CT (aka CLR124). Adult patients with new or suspected recurrence of high-grade primary or metastatic brain tumors (N = 27) were injected with [124I]CLR1404 followed by PET/CT at 6, 24, and 48h. Standard uptake values (SUV) and TBR values were calculated for all time points. Uptake of [124I]CLR1404 was qualitatively assessed, compared with magnetic resonance imaging (MRI), and correlated with clinical outcome. Final diagnosis (N = 25) was established based on surgically resected tissue or long-term follow-up. Positive uptake with high TBR was detected in all but one patient with a final diagnosis of primary/recurrent brain tumor (12/13) and in less than half of patients with treatment-related changes (5/12). Concordance between [124I]CLR1404 uptake and contrast enhancement on MRI was seen in < 40%, with no concordance between T2-hyperintensities and uptake. No significant difference in overall outcome was found between patients with and without [124I]CLR1404 uptake. The uptake pattern in these patients suggests a very high sensitivity of [124I]CLR1404 PET/CT for diagnosing tumor tissue; however, tumor specificity needs to be further defined. Relative lack of concordance with standard MRI characteristics suggests that [124I]CLR1404 PET/CT provides additional information about brain tumors compared to MRI alone, potentially improving clinical decision-making.

Glioblastoma in a patient with tuberous sclerosis

Tuberous sclerosis complex (TSC) is a multisystem, autosomal dominant disorder with a wide clinical spectrum. The most common brain tumor associated with TSC is the low grade subependymal giant cell astrocytoma. Reports of high grade primary brain tumors in patients with TSC are rare. TSC1/2 mutation has been identified in glioblastoma (GBM) even though it probably does not increase the overall risk for GBM in patients with TSC. We present a 58-year-old patient with known TSC, admitted for new neurological symptoms, diagnosed with a large heterogeneous tumor involving most of the corpus callosum. Stereotactic needle brain biopsy confirmed the diagnosis to be GBM. Five previously reported similar cases are reviewed, reflecting diversity in clinical and radiological findings and indicating that a high index of clinical suspicion must be maintained in patients with TSC.

Pretreatment serum lactate level as a prognostic biomarker in patients undergoing supratentorial primary brain tumor resection.

IntroductionMalignant primary brain tumors are one of the most aggressive cancers. Pretreatment serum nonneuronal biomarkers closely associated with postoperative outcomes are of high clinical relevance. The present study aimed to identify potential pretreatment serum biomarkers that may influence oncological outcomes in patients with primary brain tumors.MethodsA total of 74 patients undergoing supratentorial primary brain tumor resection were enrolled. Before tumor resection, serum neuronal biomarkers, namely neuron-specific enolase (NSE), S100β, and glial fibrillary acidic protein (GFAP), and serum nonneuronal biomarkers, namely neutrophil gelatinase-associated lipocalin (NGAL), lactate dehydrogenase (LDH), and lactate, were measured and associated postoperative oncological outcomes, including brain tumor grading, progression-free survival (PFS), and overall survival (OS), were compared.ResultsPatients with high-grade brain tumors had significantly higher pretreatment serum lactate levels (p = 0.011). By contrast, other biomarkers were comparable between patients with high-grade and low-grade brain tumors. Receiver operating characteristic curve analysis of serum lactate levels yielded an area under the curve of 0.71 for differentiating between high-grade and low-grade brain tumors. Kaplan–Meier survival analysis revealed patients with high serum lactate levels (≧2.0 mmol/L) had shorter PFS and OS (p = 0.021 and p = 0.093, respectively). In a multiple regression model, only elevated serum lactate levels were associated with poor PFS and OS (p = 0.021 and p = 0.048, respectively).ConclusionsAn elevated pretreatment serum lactate level is a prognostic biomarker of high-grade primary brain tumors and is significantly associated with poor PFS in patients with supratentorial brain tumors undergoing tumor resection. By contrast, other serum biomarkers are not significantly associated with oncological outcomes.

Incidence trends in high-grade primary brain tumors in males and females.

The focus of the present review is to investigate whether there is a variation in the incidence rates between male and female patients with high-grade primary brain tumors and if there are altered incidence rates associated with the time at which they were diagnosed. Previous studies identified in internationally peer-reviewed journals were identified using a systematic search of the PubMed database. Due to the difficulties in data interpretation, studies that exclusively included patient data classified prior to the 2nd edition of the World Health Organization histological classification system of brain tumors were excluded. The overall incidence rates and incidence trends of male and female patients were analyzed separately. The mean age-adjusted overall incidence rate in the male population was 1.27 per 100,000 compared with 0.89 per 100,000 in the female population. The variance between the two genders differed and a Wilcoxon rank-sum test indicated that there was no significant difference in the incidence rate of high-grade primary brain tumors between males and females (P=0.3658). Furthermore, there was no significant difference in incidence rate trend between 1996-2004 and 2005-2010 for male or female populations (P=0.101 and P=0.472, respectively). The results from the present systematic review did not demonstrate a significant difference in incidence rate between the two genders. Therefore, the results from the current study are considered to be preliminary and further studies are required to elucidate this issue.

Intranasal Oncolytic Virotherapy with CXCR4-Enhanced Stem Cells Extends Survival in Mouse Model of Glioma.

SummaryThe challenges to effective drug delivery to brain tumors are twofold: (1) there is a lack of non-invasive methods of local delivery and (2) the blood-brain barrier limits systemic delivery. Intranasal delivery of therapeutics to the brain overcomes both challenges. In mouse model of malignant glioma, we observed that a small fraction of intranasally delivered neural stem cells (NSCs) can migrate to the brain tumor site. Here, we demonstrate that hypoxic preconditioning or overexpression of CXCR4 significantly enhances the tumor-targeting ability of NSCs, but without altering their phenotype only in genetically modified NSCs. Modified NSCs deliver oncolytic virus to glioma more efficiently and extend survival of experimental animals in the context of radiotherapy. Our findings indicate that intranasal delivery of stem cell-based therapeutics could be optimized for future clinical applications, and allow for safe and repeated administration of biological therapies to brain tumors and other CNS disorders.

Role of TRPV1 Channels in Glioma Cell Viability and Survival

High grade primary brain tumors are among the deadliest malignancies known to medicine. Anaplastic gliomas (WHO grade 3) and Glioblastoma Multiforme, or GBM, (WHO grade 4) are prevalent primary brain tumors in adults. Exploration of new avenues in treatment of GBM is absolutely crucial when taking into consideration the short (12-17 months) survival time after the diagnosis. Annually there are around 20,000 new cases, including over 4,000 pediatric (age 0-19) cases. The heat and capsaicin receptor TRPV1 is highly expressed in malignant gliomas, where the channels are thought to play a role in inducing apoptotic cell death. We evaluated TRPV1 expression in different glioma cell lines and determined the correlation of the protein expression with age and sex in the tissue samples obtained from patients with GMB. We found that age dependent correlation of TRPV1 expression is more characteristic for male patients with GBM than for females. However, in both groups TRPV1 expression was higher in patients of age 35-55 years old.We also investigated the sensitivity of different glioma cell lines to the TRPV1 agonists, including endovanilloid NADA and capsaicin. We found that 50 μM of capsaicin inhibited the cell growth and proliferation of U87 but not U251 glioma cells. The presence of TRPV1 on the plasma membrane was higher in U87 cells in comparison to U251, as confirmed by biotinylation, and may account for the effect of capsaicin on the cell viability. These results indicate that TRPV1 could play an important role in regulating Ca2+ homeostasis of primary brain tumors.

Molecular Mechanism of TRPV1 Activation by Capsaicin

Molecular Mechanism of TRPV1 Activation by Capsaicin

Development of venous thromboembolism (VTE) in patients undergoing surgery for brain tumors: Results from a single center over a 10 year period

Patients who undergo craniotomy for brain neoplasms have a high risk of developing venous thromboembolism (VTE), including deep vein thromboses (DVT) and pulmonary emboli (PE). The reasons for this correlation are not fully understood. This retrospective, single-center review aimed to determine the risk factors for VTE in patients who underwent neurosurgical resection of brain tumors at Northwestern University from 1999 to 2010. Our cohort included 1148 patients, 158 (13.7%) of whom were diagnosed with DVT and 38 (3.3%) of whom were diagnosed with PE. A variety of clinical factors were studied to determine predictors of VTE, including sex, ethnicity, medical co-morbidities, surgical positioning, length of hospital stay, tumor location, and tumor histology. Use of post-operative anticoagulants and hemorrhagic complications were also investigated. A prior history of VTE was found to be highly predictive of post-operative DVT (odds ratio [OR]=7.6, p=0.01), as was the patient’s sex (OR=14.2, p<0.001), ethnicity (OR=0.5, p=0.04), post-operative intensive care unit days (OR=0.2, p=0.003), and tumor histology (OR=−0.16, p=0.01). Contrary to reports in the literature, the data collected did not indicate that the administration of post-operative medical prophylaxis for VTE was significant in preventing their formation (OR=−0.14, p=0.76). Hemorrhagic complications were low (2.2%) and resultant neurologic deficit was lower still (0.7%). The study indicates that patients with high-grade primary brain tumors and metastatic lesions should receive aggressive preventative measures in the post-operative period.

IT-19 * TEMOZOLAMIDE RESISTANT INNATE LYMPHOCYTES ADMINISTERED DURING CHEMOTHERAPY IMPROVE SURVIVAL IN HIGH-GRADE GLIOMA

Conventional treatment strategies for high-grade primary brain tumors have failed to consistently extend median survival beyond two years. Using a human/mouse xenograft model, we report improved survival using a combination of Temozolomide (TMZ) chemotherapy with a Drug Resistant Cellular Immunotherapy (DRI) consisting of activated MGMT-transduced γδ T cells and NK cells. MGMT genetic engineering enables cytotoxic lymphocyte function in a chemotherapy-rich environment at a time when the tumor is maximally stressed. Intracranial (IC) glioma xenografts were established using either unmodified (P) or a TMZ-resistant clone (T) of human GBM-X12 primary explants propagated in mice. Tumor-bearing mice were treated i.p. with 60mg/kg TMZ on days 6, 8,13, and 15 post-tumor placement and received IC injection of 1 x 106 MGMT-modified DRI on post-injection days 7 and 14. Control mice received non-modified cells, TMZ alone or no therapy. Survival was assessed using Kaplan-Meier analysis. Both GBM-X12P and X12T express stress antigens MIC-A, MIC-B, and ULBP-4 with only ULBP-4 slightly upregulated on X12T upon exposure to TMZ. Both tumors were killed by expanded/activated γδ T cells in vitro at approximately 80% at an effector : target ratio of 20:1. Cell therapy alone did not improve survival beyond that of untreated mice for either tumor. For the unmodified tumor X12P, both TMZ therapy and TMZ + DRI significantly improved survival over untreated controls (p < 0.001), and the combined therapy increased median survival from 57 to 75 days over TMZ alone. Combined therapy with TMZ + DRI also improved survival for X12T (p = 0.0147) over untreated controls, and showed a marginal improvement over TMZ alone (p = 0.0966) and improvement in median survival from 22 to 25 days. In summary, the combination of chemotherapy-induced stress antigen expression and targeted DRI significantly increases time to progression and improves survival in tumor-bearing immunodeficient mice.

Use of fluorescence to guide resection or biopsy of primary brain tumors and brain metastases

The accurate discrimination between tumor and normal tissue is crucial for determining how much to resect and therefore for the clinical outcome of patients with brain tumors. In recent years, guidance with 5-aminolevulinic acid (5-ALA)-induced intraoperative fluorescence has proven to be a useful surgical adjunct for gross-total resection of high-grade gliomas. The clinical utility of 5-ALA in resection of brain tumors other than glioblastomas has not yet been established. The authors assessed the frequency of positive 5-ALA fluorescence in a cohort of patients with primary brain tumors and metastases. The authors conducted a single-center retrospective analysis of 531 patients with intracranial tumors treated by 5-ALA-guided resection or biopsy. They analyzed patient characteristics, preoperative and postoperative liver function test results, intraoperative tumor fluorescence, and histological data. They also screened discharge summaries for clinical adverse effects resulting from the administration of 5-ALA. Intraoperative qualitative 5-ALA fluorescence (none, mild, moderate, and strong) was documented by the surgeon and dichotomized into negative and positive fluorescence. A total of 458 cases qualified for final analysis. The highest percentage of 5-ALA-positive fluorescence in open resection was found in glioblastomas (96%, n = 99/103). Among other tumors, 5-ALA-positive fluorescence was detected in 88% (n = 21/32) of anaplastic gliomas (WHO Grade III), 40% (n = 8/19) of low-grade gliomas (WHO Grade II), no (n = 0/3) WHO Grade I gliomas, and 77% (n = 85/110) of meningiomas. Among metastases, the highest percentage of 5-ALA-positive fluorescence was detected in adenocarcinomas (48%, n = 13/27). Low rates or absence of positive fluorescence was found among pituitary adenomas (8%, n = 1/12) and schwannomas (0%, n = 0/7). Biopsies of high-grade primary brain tumors showed positive rates of fluorescence similar to those recorded for open resection. No clinical adverse effects associated with use of 5-ALA were observed. Only 1 patient had clinically silent transient elevation of liver enzymes. Study findings suggest that the administration of 5-ALA as a surgical adjunct for resection and biopsy of primary brain tumors and brain metastases is safe. In light of the high rate of positive fluorescence in high-grade gliomas other than glioblastomas, meningiomas, and a variety of metastatic cancers, 5-ALA seems to be a promising tool for enhancing intraoperative identification of neoplastic tissue and optimizing the extent of resection.

Anosmin-1 contributes to brain tumor malignancy through integrin signal pathways

Anosmin-1, encoded by the KAL1 gene, is an extracellular matrix (ECM)-associated protein which plays essential roles in the establishment of olfactory and GNRH neurons during early brain development. Loss-of-function mutations of KAL1 results in Kallmann syndrome with delayed puberty and anosmia. There is, however, little comprehension of its role in the developed brain. As reactivation of developmental signal pathways often takes part in tumorigenesis, we investigated if anosmin-1-mediated cellular mechanisms associated with brain tumors. Our meta-analysis of gene expression profiles of patients' samples and public microarray datasets indicated that KAL1 mRNA was significantly upregulated in high-grade primary brain tumors compared with the normal brain and low-grade tumors. The tumor-promoting capacity of anosmin-1 was demonstrated in the glioblastoma cell lines, where anosmin-1 enhanced cell motility and proliferation. Notably, anosmin-1 formed a part of active β1 integrin complex, inducing downstream signaling pathways. ShRNA-mediated knockdown of anosmin-1 attenuated motility and growth of tumor cells and induced apoptosis. Anosmin-1 may also enhance the invasion of tumor cells within the ECM by modulating cell adhesion and activating extracellular proteases. In a mouse xenograft model, anosmin-1-expressing tumors grew faster, indicating the role of anosmin-1 in tumor microenvironment in vivo. Combined, these data suggest that anosmin-1 can facilitate tumor cell proliferation, migration, invasion, and survival. Therefore, although the normal function of anosmin-1 is required in the proper development of GNRH neurons, overexpression of anosmin-1 in the developed brain may be an underlying mechanism for some brain tumors.

Epilepsy in primary cerebral tumors: The characteristics of epilepsy at the onset (results from the PERNO study – Project of Emilia Romagna Region on Neuro‐Oncology)

To present new information on the semiology and short-term evolution of seizures associated with primary brain tumors (PBTs) in a prospective study. This study is a section of the PERNO study--Project of Emilia Romagna Region on Neuro-Oncology, the main aim of which is to collect prospectively all cases of PBTs occurring in the Emilia-Romagna region, northeast Italy (3,983,346 population) from January 2009 to December 2011, to allow epidemiologic, clinical, and biomolecular studies. The epilepsy section of the PERNO study included all the patients who experienced seizures, either as first symptom of the tumor or appearing during the course of the disease. Each patient was interviewed by the referring neurologist with a specific interest in epilepsy. The patients who entered the study were followed up with visits on a quarterly basis. We collected 100 cases with full clinical, neuroradiologic, and pathologic data. The majority (79%) had high grade PBTs (glioblastoma in 50 cases), whereas the remaining patients had low-grade gliomas, mostly localized in the frontal (60%), temporal (38%), and parietal (28%) lobes. Seizures were the first symptom of the tumor in 72 cases. Overall, the initial seizures were tonic-clonic (48%) (without clear initial focal signs in more than half of the patients), focal motor (26%), complex partial (10%), and somatosensitive (8%). The majority of cases (60%) had isolated seizures or a low seizure frequency at the onset of the disease, whereas a high seizure frequency or status epilepticus was observed in 18% and 12% of cases, respectively. Ninety-two patients underwent surgical removal of the tumor, which was either radical (38%) or partial (53%). Seven patients underwent only cerebral biopsy. In the 72 patients in whom seizures were the first symptom, the mean time to the surgical treatment was 174 days, with a significant difference between high grade (95 days) and low grade (481 days) gliomas. At the time of our first observation, the majority of patients (69%) had already undergone surgical removal, with a mean follow-up of 3 months after the procedure. Overall, 39 patients (56%) were seizure free after tumor removal. The good outcome did not depend on presurgical seizure frequency or tumor type, although there was a trend for better results with low-grade PBTs. These data provide evidence that seizures are strictly linked to the tumoral lesion: They are the initial symptom of the tumor, reflect the tumor location and type, are usually resistant to antiepileptic treatment, and may disappear after the treatment of the lesion.

EMMPRIN expression positively correlates with WHO grades of astrocytomas and meningiomas

High-grade primary brain tumors possessed poor outcome due to invasiveness. Extracellular matrix metalloproteinase inducer (EMMPRIN) stimulates peri-tumoral fibroblasts to secrete matrix metalloproteinase and promote invasiveness. This study hypothesized that high-grade brain tumors overexpress EMMPRIN. Analyzing the public delinked database from the Gene Expression Omnibus profile, the results showed that the EMMPRIN mRNA level was higher in WHO grade IV (n = 81) than in grade III (n = 19, p < 0.0005) astrocytomas and non-tumor brain tissue controls (n = 23, p < 0.00001). The results of tissue microarray-based immunohistochemical (IHC) staining revealed that EMMPRIN levels positively correlated with WHO grades for astrocytomas (p = 0.008) and meningiomas (p = 0.048). EMMPRIN mRNA levels in conventional glioma cell lines (n = 36) was not less than those in glioma primary culture cells (n = 27) and glioblastoma stem-like cells (n = 12). The GBM8401, U87MG, and LN229 human glioma cell lines also overexpressed EMMPRIN. Hematoxylin and eosin, IHC, and immunofluorescence staining of xenografts confirmed that high-grade brain tumors overexpressed EMMPRIN. Lastly, Kaplan–Meier analysis revealed poorer survival in WHO grade IV (n = 56) than in grade III astrocytomas (n = 21, by log-rank test; p = 0.0001, 95 % CI: 1.842–3.053). However, in high-grade astrocytomas, there was no difference in survival between high and low EMMPRIN mRNA levels. Thus, this study identified that high-grade brain tumors overexpress EMMPRIN, which positively correlates with WHO grades in human astrocytomas and meningiomas, and suggests that EMMPRIN may be a therapeutic target of brain tumor.

Improved Conspicuity and Delineation of High-Grade Primary and Metastatic Brain Tumors Using “Restriction Spectrum Imaging”: Quantitative Comparison with High B-Value DWI and ADC

Restriction spectrum imaging is a sensitive DWI technique for probing separable water diffusion compartments in tissues. Here, we evaluate RSI-CMs derived from the spherically-restricted water compartment for improved tumor conspicuity and delineation from nontumor tissue and reduced sensitivity to edema compared with high-b-value DWI and ADC. RSI was performed in 10 presurgical patients: 4 with glioblastoma, 3 with primary CNS lymphoma, and 3 with metastatic brain tumors. Multidirectional DWI data were collected at b = 500, 1500, and 4000 s/mm(2). Quantification of tumor conspicuity, edema conspicuity, and relative sensitivity to edema for RSI-CMs; DWI at b = 4000 (DWI-4000); and ADC were compared in manually drawn VOIs. Receiver operating characteristic curves were used to evaluate the sensitivity and specificity of each method for delineating tumor from normal-appearing WM. Significant TC was seen with both RSI-CMs and DWI-4000, but not ADC. Significant EC was seen with ADC, but not RSI-CMs or DWI-4000. Significantly greater TC was seen with RSI-CMs compared with DWI-4000. Significantly reduced RSE was seen with RSI-CMs compared with both DWI-4000 and ADC. Greater sensitivity and specificity for delineating tumor from normal-appearing WM were seen with RSI-CMs (AUC = 0.91) compared with both DWI-4000 (AUC = 0.77) and ADC (AUC = 0.66). RSI-CMs offer improved conspicuity and delineation of high-grade primary and metastatic brain tumors and reduced sensitivity to edema compared with high-b-value DWI and ADC.

Neurokognitive Beeinträchtigungen bei Patienten mit malignen Hirntumoren

This article reviews research on neurocognitive deficits in adult patients with malignant brain tumors, i. e. high-grade primary brain tumors and brain metastases. Brain tumor patients experience significant neurocognitive deficits, mainly in the domains of attention, memory, executive function and psychomotor function. Neurosurgical, radiotherapeutic or radiochemotherapeutic treatment regimens are often associated with a decline in cognitive functioning. However, such empirical observations are often confounded with the neurocognitive effects of tumor progression. Few studies investigated associations among neurocognitive deficits and distress. These studies revealed contradictory results. Similarly, research on neurocognitive deficits and health-related quality of life has resulted in equivocal evidence. Furthermore, convincing empirical evidence for the effectiveness of neurocognitive training in patients with high-grade brain tumors is lacking.

DAB389EGF fusion protein therapy of refractory glioblastoma multiforme.

Primary brain tumors including anaplastic astrocytomas and glioblastoma multiforme are difficult to treat because of their locally invasive nature and chemoradioresistance. Novel therapies are needed. One class of therapeutics is fusion proteins consisting of peptide toxins fused to brain tumor selective ligands. DAB389EGF is a fusion protein composed of the catalytic and translocation domains of diphtheria toxin fused via a His-Ala linker to human epidermal growth factor (EGF). DAB389EGF is selectively toxic to EGF receptor (EGFR) overexpressing cells. Close to half of all high-grade primary brain tumors have EGFR gene amplification and EGFR overexpression. With the use of convection-enhanced delivery (CED), DAB389EGF may be delivered locally at high concentrations to the brain tumor. CED would avoid many of the pharmacologic and toxicologic barriers which have limited effective use of this agent including rapid clearance from the circulation, high anti-diphtheria toxin antibody titers in the blood and toxicities to the liver and kidney. Both cell lines and animal models are available to assess the potential of this agent for brain tumor therapy. Since significant amounts of clinical grade DAB389EGF are available, some careful additional preclinical efficacy work should lead to testing of this agent in patients within the next few years.

Consistent and Selective Expression of the Discoidin Domain Receptor-1 Tyrosine Kinase in Human Brain Tumors

Few molecular targets are both consistently and selectively expressed in a majority of central nervous system (CNS) neoplasms. Receptor tyrosine kinases have been implicated in brain tumor oncogenesis. We previously isolated one such receptor, discoidin domain receptor-1 (DDR1), from high-grade pediatric brain tumors. Here, we analyze the cellular origin and distribution of DDR1 expression in human brain tumors and its expression in tumor cells relative to surrounding brain.By use of a digoxigenin-labeled DDR1 riboprobe, we investigated the expression of DDR1 messenger ribonucleic acid in a prospective series of 30 resected human primary and metastatic brain neoplasms, nonneoplastic human brain, and mouse embryonic brain, as well as a mouse glioblastoma model, by in situ hybridization.All the high-grade primary brain and metastatic brain tumors showed unequivocal, intense DDR1 expression within the majority of tumor cells, whereas expression was not observed in hyperplastic tumor blood vessels, normal brain blood vessels, inflammatory cells, or in the normal brain tissue that surrounded the tumor. Receptor expression was limited to tumor cells located within solid tumor tissue. Overall, 27 of 29 resected CNS tumors exhibited tumor cell-specific DDR1 expression, whereas one specimen composed of isolated glioblastoma cells within invaded brain parenchyma showed no detectable staining for this receptor. DDR1 was also expressed preferentially in the ventricular zone (a region of highly proliferating precursor cells) of mice at embryonic Day 15.5.We found that DDR1 is consistently expressed in all high-grade brain neoplasms studied and is selective for tumor cells in the specimens analyzed. The expression of DDR1 by tumor cells of CNS neoplasms and by primitive cells of the embryonic ventricular zone suggests that DDR1 is a potentially useful marker of tumor cells within the CNS.