Primary Glial Brain Tumors Research Articles

Amide proton transfer weighted (APTw) imaging based radiomics allows for the differentiation of gliomas from metastases

We sought to evaluate the utility of radiomics for Amide Proton Transfer weighted (APTw) imaging by assessing its value in differentiating brain metastases from high- and low grade glial brain tumors. We retrospectively identified 48 treatment-naïve patients (10 WHO grade 2, 1 WHO grade 3, 10 WHO grade 4 primary glial brain tumors and 27 metastases) with either primary glial brain tumors or metastases who had undergone APTw MR imaging. After image analysis with radiomics feature extraction and post-processing, machine learning algorithms (multilayer perceptron machine learning algorithm; random forest classifier) with stratified tenfold cross validation were trained on features and were used to differentiate the brain neoplasms. The multilayer perceptron achieved an AUC of 0.836 (receiver operating characteristic curve) in differentiating primary glial brain tumors from metastases. The random forest classifier achieved an AUC of 0.868 in differentiating WHO grade 4 from WHO grade 2/3 primary glial brain tumors. For the differentiation of WHO grade 4 tumors from grade 2/3 tumors and metastases an average AUC of 0.797 was achieved. Our results indicate that the use of radiomics for APTw imaging is feasible and the differentiation of primary glial brain tumors from metastases is achievable with a high degree of accuracy.

EXTH-50. ACTIVATION OF THE MITOCHONDRIAL CLPP PROTEASE IS SYNTHETICALLY LETHAL WITH HDAC1/2 INHIBITION IN GLIOBLASTOMA MODEL SYSTEMS

Abstract Novel therapeutic targets are critical to unravel for recalcitrant malignancies, such as the most common primary brain tumor in adults, glioblastoma (GBM). Heterogeneity remains a hallmark of primary glial brain tumors and therefore targeting several pathways simultaneously is an appropriate approach. Here, we showed that pharmacological activation of the mitochondrial ClpP protease through utilization of the novel imipridone compounds (ONC206 and ONC212) in combination with global (Panobinostat) and selective (romidepsin) HDAC – inhibitors caused synergistic reduction of viability in established and patient-derived xenograft (PDX) cultures of human GBM. This effect occurred independent of TP53 status and was partially mediated by activation of a cell death with apoptotic features accompanied by activation of initiator and effector caspases as well as cleavage of PARP. Consistently, the combination treatment altered the expression of anti-apoptotic and pro-apoptotic Bcl-2 family members, resulting in down-regulation of Bcl-xL and Mcl-1. Knockdown experiments targeting Noxa, BIM, Bcl-xL and Mcl-1 confirmed a functional implication of these proteins in the reduction of cellular viability mediated by the combination treatment. Importantly, knockdown of the ClpP protease significantly rescued the reduction of cellular viability by ClpP activators and the combination treatment, respectively, suggesting critical involvement of this protein. Finally, using a PDX model, we demonstrated that the combination treatment of romidepsin and ONC206 reduced tumor growth more potently than single treatments or vehicle by enhanced reduction of cellular proliferation and pronounced induction of cell death in vivo. Collectively, these observations suggest that the efficacy of HDAC-inhibitors might be significantly enhanced through ClpP activators in model systems of human GBM.

Seroprevalence to herpesviruses in patients with primary brain gliomas

Purpose of the study . The purpose of the study was to assess the level of seroprevalence and the frequency of detection of serological markers of acute herpesvirus infection in patients with PGBT in comparison with those in patients with chronic non-tumor diseases. Materials and methods . Before conducting antitumor therapy, the blood serum of 42 patients with PGBT (the main group) was studied. The comparison group consisted of 137 patients with chronic non-tumor diseases. Antibodies of classes M and G to herpes simplex virus types 1, 2 (HSV-1,2), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpes virus type 6 (HHV-6) were determined by ELISA using JSC Vector-Best reagent kits. Results . Among patients with PGBT, seropositive for HSV-1,2 were 95.2%, CMV — 92.9%, EBV — 100%, HHV-6-40.5% of patients. No statistically significant differences in seroprevalence and the presence of markers of acute infection (IgM) were found either in comparison with non-tumor diseases or depending on the malignancy grade. Antibodies to HSV-1,2, CMV and EBV in patients with gliomas were significantly more often found in the medium range, and in the comparison group — in the high values of coefficient of positivity (CP) for IgG. In all the studied groups, antibodies to HHV-6 were determined statistically significantly less frequently than to other herpes viruses. Conclusion . The absence of statistically significant differences in seropositivity between groups of patients and their presence between pathogens is most likely a reflection of general trends in the population, and the question of the involvement of various representatives of the Herpesviridae family in neuro-oncogenesis of primary glial brain tumors still remains open.

PLSCR1 and XKR8: New markers for low-grade glioma progression and outcome

Abstract Background One of the most frequently diagnosed oncological diseases among young persons is Low-grade glioma (LGG). More than 80% of LGGs progress to higher-grade tumors always lethal to a patient. LGG is an extremely heterogeneous group of primary glial brain tumors with a quite variable rate of recurrence, survival, and response to treatment. Thus a study of new biomarkers associated with disease progression and patient outcome is useful to improve patient management. Genes involved in key cellular processes, e.g., apoptosis, are promising prognostic and predictive cancer markers. Phosphatidylserine (PS) plays an essential role in apoptosis signaling. Several studies suggested PS is dysregulated in the tumor microenvironment and offends the development of anti-cancer immune response. The scramblases PLSCR1 and XKR8 allegedly could be associated with the progression and outcome of LGG since they could be involved in the development of immunity via regulation of PS activity by its bidirectional translocation in the plasma membrane. Thus this study was aimed to evaluate associations of PLSCR1 and XKR8 with disease-free and overall survival of LGG patients. Methods Gene expression values and clinical information of 530 LGG patients were downloaded from TCGA Low-Grade Glioma study using the public resource CBioPortal. According to gene expression values (RNA Seq V2 RSEM) patients were divided into two groups: with downregulated ( mean) PLSCR1 or XKR8 gene. The Kaplan-Meier procedure and Log-Rank test were used for survival analysis. All calculations were performed in the integrated development environment - RStudio. Results It was shown the LGG patients with upregulated PLSCR1 (p = 2.54e-14) and XKR8 (p = 7.33e-15) gene had worse disease prognosis than other patients. Similar associations were seen in the study of LGG progression, where patients with upregulated PLSCR1 (p = 7.75e-07) and XKR8 (p = 5.59e-10) gene had a higher risk of cancer recurrence. Conclusions Consequently, PLSCR and XKR8 genes could be considered as new prognostic biomarkers of LGG progression and outcome. Legal entity responsible for the study Research Laboratory Biomarker. Funding The work was performed according to the Russian Government Program of Competitive Growth of KFU. Disclosure All authors have declared no conflicts of interest.

Proton 3D MR spectroscopy in the diagnosis of glial brain tumors

The purpose of this study was an assessment of the proton 3D MR spectroscopy efficacy in diagnosis of primary glial brain tumors.Material and methods. Sixty three patients aged from 20 to 60 years with primary glial brain tumors of varying degrees of malignancy were examined. The ratios of main metabolites indices were evaluated with following comparison with the metabolites obtained in gray and white matter of the opposite hemisphere.The ratios of main metabolites: Cho/Cr, NAA/Cr, Cho/NAA showed significant (p <0.005) differences in the groups of patients with low and high grade gliomas.Results. The obtained data proved the efficacy of the proton 3D MR-spectroscopy in predicting of the glial brain tumors malignancy.

P21-F Motor cortex mapping in patients with primary glial brain tumors and structural epilepsy

Background Glial brain tumors (GBT) adjacent to motor cortical areas (MCA) are associated with tumor-related epilepsy (TRE). We analyzed aspects of intraoperative motor mapping (IOMM) in the presence of epileptiform activity in the peritumoral zone. Material and methods We studied 41 patients (m/f = 18/23, age 18–77) with GBT located in the MCA were analyzed. All patients underwent tumor resection in Polenov Russian Neurosurgical Institute in 2014–2016. IOMM was performed utilizing “IOM ISIS” hardware (Inomed, Germany). The trial group included 30 patients with TRE. Eleven patients in control group had GBT without TRE. Motor function was assessed postoperatively according to a conventional 6-grade score. Impairment degree and duration were estimated. Results The presence of TRE does not reduce the possibility of the motor response during IOMM (odds ratio – 1.0 (95% confidence interval 0.2 – 4.3)). However, current levels sufficient for IOMM in the trial group were significantly higher than in control group (22 – 25 mA vs 16 – 20 mA respectively; p Conclusions IOMM in patients with TRE is performed while motor neurons are in the state of altered reactivity. This state is associated with higher current levels for IOMM. It may also contribute to a more significant transient motor deficit in the early postoperative period.

Pharmacotherapeutic Management of Pediatric Gliomas

Primary glial brain tumors account for the majority of primary brain tumors in children. They are classified as low-grade gliomas (LGG) or high-grade gliomas (HGG), based on specific pathologic characteristics of the tumor, resulting in disparate clinical prognoses. Surgery is a mainstay of treatment for HGG, although it is not curative, and adjuvant therapy is required. Temozolomide, an oral imidazotetrazine prodrug, while considered standard of care for adult HGG, has not shown the same degree of benefit in the treatment of pediatric HGG. There are significant biologic differences that exist between adult and pediatric HGG, and targets specifically aimed at the biology in the pediatric population are required. Novel and specific therapies currently being investigated for pediatric HGG include small molecule inhibitors of epidermal growth factor receptor, platelet-derived growth factor receptor, histone deacetylase, the RAS/AKT pathway, telomerase, integrin, insulin-like growth factor receptor, and γ-secretase. Surgery is also the mainstay for LGG. There are defined front-line, multiagent chemotherapy regimens, but there are few proven second-line chemotherapy options for refractory patients. Approaches such as the inhibition of the mammalian target of rapamycin pathway, inhibition of MEK1 and 2, as well as BRAF, are discussed. Further research is required to understand the biology of pediatric gliomas as well as the use of molecularly targeted agents, especially in patients with surgically unresectable tumors.

Atypical Presentation of Oligodendroglioma Masquerading as a Primary CNS Lymphoma (P03.141)

Objective: To present and discuss a case of right frontal oligodendroglioma showing clinical response to steroid therapy. Background Oligodendrogliomas are primary glial brain tumors that constitute 2-5% of all primary CNS neoplasms. They usually present as a solitary brain tumor in adults and can, at times, be confused with a primary CNS lymphoma at presentation. Design/Methods: Case Report. Results: A 52-year-old female presented with partial complex seizures. MRI of the brain revealed a medial right frontal lesion, mild falcine herniation and a significant T2 abnormality with faint heterogeneous enhancement. She underwent a repeat imaging following a few weeks of treatment with steroids and an antiepileptic drug. An interval decrease in enhancement of the lesion and a reduction in the mass effect was seen. After six months, the patient discontinued steroids due to intolerable side effects. There was a recurrence of seizures on discontinuation of steroids and a repeat imaging revealed an infiltrating mass lesion within the right anterior medial frontal lobe, an extension into the uncus of temporal lobe and involvement of genu of the corpus callosum. The patient underwent a stereotactic serial biopsy that showed grade 2-3 oligodendroglioma. Real time PCR, performed for markers on chromosomes 1p and 19q, showed a loss at both chromosomal arms. She was started on procarbazine, lomustine and vincristine (PCV) chemotherapy along with radiation and adjuvant temozolamide, and achieved a clinical remission. She stays in clinical remission and is seizure free 8 years after initial presentation. Conclusions: Steroid responsiveness has not been described in primary oligodendrogliomas. Though the patient had contrast enhancement and seizures at presentation, both indicators of poor prognosis with this tumor; she achieved and maintained clinical remission. It is possible that in addition to combined 1p/19q loss, steroid responsiveness may be a marker of favorable prognosis in this case. Disclosure: Dr. Anand has nothing to disclose. Dr. Conrad has nothing to disclose.

Glioblastoma Multiforme Regional Genetic and Cellular Expression Patterns: Influence on Anatomic and Physiologic MR Imaging

To determine whether magnetic resonance (MR) imaging is influenced by genetic and cellular features of glioblastoma multiforme (GBM) aggressiveness. In this HIPAA-compliant institutional review board-approved study, multiple enhancing and peritumoral nonenhancing stereotactic neurosurgical biopsy samples from treatment-naïve GBMs were collected prospectively, with guidance from cerebral blood volume (CBV) MR imaging measurements. By using monoclonal antibodies, tissue specimens were examined for microvascular expression, hypoxia, tumor and overall cellular density, and histopathologic features of GBM aggressiveness. Genetic expression patterns were investigated with RNA microarrays. Imaging and histopathologic variables were compared with the Welch t test and Pearson correlations. Microarray analysis was performed by using false discovery rate (FDR) statistics. Tumor biopsy of 13 adult patients yielded 16 enhancing and 14 peritumoral nonenhancing specimens. Enhancing regions had elevated relative CBV and reduced relative apparent diffusion coefficient (ADC) measurements compared with peritumoral nonenhancing biopsy regions (P < .01). A positive correlation was found between relative CBV and all histopathologic features of aggressiveness (P < .04). An inverse correlation was found between relative ADC and all histopathologic features of aggressiveness (P < .05). RNA expression patterns between tumor regions were found to be significantly different (FDR < 0.05), with hierarchical clustering by biopsy region only. These findings suggest MR imaging is significantly influenced by GBM genetic and cellular biologic features of aggressiveness and imply physiologic MR imaging may be useful in pinpointing regions of highest malignancy within heterogeneous tissues, thus facilitating histologic grading of primary glial brain tumors.

Diffusion and perfusion magnetic resonance imaging in evaluation of primary glial brain tumors

Diffusion (DWI) and perfusion (PWI) imaging can give important data about physiological characteristics of tissue, which complete morphologic findings from conventional MRI. The aim of this study is to estimate the value of these MRI technics in evaluation of primary glial brain tumors. The significance of DWI and PWI in differentiation of histologically proven low- and high-grade gliomas was estimated in 48 patient with diagnosed brain gliomas. ADC and rCBV values were compared by aplication of Mann-Whitney test, and logistic regression analysis was used to determine which of these two parameters contributed the most in increasing the diagnostic accuracy, ia. its sensitivity, specificity and predictive velues. ROC curves were constructed to determine threshold values for differentiation of low- from high-grade lesions. Statistical significance were showed between mean values of rCBV for low-grade (0.82) and high-grade (5.32) gliomas, which was not found for values of ADC parameters. Threshold rCBV value of 1.23 was determinated for discrimination between low- and high-grade gliomas with a sensitivity of 83.2% and a specificity of 77.5%. Conventional MRI combined with PWI increases the accuracy in determination of glioma grade.

Effect of hydrophilic components of the extracellular matrix on quantifiable diffusion-weighted imaging of human gliomas: preliminary results of correlating apparent diffusion coefficient values and hyaluronan expression level.

The purpose of this study was to evaluate the relationship between apparent diffusion coefficient (ADC) measured by MR imaging and the level of immunohistochemical expression of hyaluronan or hyaluronic acid as one of the main hydrophilic components of the extracellular matrix in brain glial tumors. Nineteen patients with primary glial brain tumors were included in the study. Mean ADC values were calculated in all tumors and were normalized with the ADC values of the contralateral normal-appearing brain ratios. All tumors underwent surgical resection, and the histologic diagnosis was based on the analysis of the surgical specimen. Mean values of the labeling index of hyaluronan (LI-HA) were calculated to determine quantifiably the histochemical expression of hyaluronan in the tumor. The mean ADC values and the mean ADC ratios (ADC(ratio)) of the tumors were then correlated to the mean values of the LI-HA. The mean ADC (93 x 10(-5) mm(2)/sec) and the mean ADC(ratio) (1.25) of the high-grade glial tumors were significantly lower than the mean ADC (123 x 10(-5) mm/sec) and the mean ADC(ratio) (1.64) of the low-grade glial tumors (p < 0.01). The mean LI-HA (72.8%) was also significantly lower in the high-grade gliomas than the mean LI-HA (93.4%) in the low-grade gliomas (p < 0.001). A positive correlation was found between mean ADC values and the mean LI-HA (tau = 0.35, p < 0.05) and also between the mean ADC(ratio) and the mean LI-HA (tau = 0.33, p < 0.05). Hyaluronan as one of the main hydrophilic components of the extracellular matrix in gliomas likely contributes to differences in the ADC values between high- and low-grade glial tumors.