Primary Glial Tumors Research Articles

The Role of Survivorship Care for Patients with Glioma.

To discuss the role of survivorship care and survivorship care plans, including a recently developed neuro-oncology-specific plan care (https://www.soc-neuro-onc.org/SNO/Resources/Survivorship_Care_Plan.aspx) for adult patients diagnosed with primary glial neoplasms and the necessary educational needs of oncology nurses. Published peer-reviewed literature and resources from cancer and neuro-oncology professional organizations and patient advocacy organizations. The current Commission on Cancer mandates adult cancer patients treated with curative intent each receive an individualized survivorship care plan. Patients with glioma are likely to benefit from receiving survivorship care, including survivorship care plans aimed at addressing the complex and evolving needs of this unique patient population throughout their illness trajectory. Nurse professionals are critical to the development and implementation of cancer survivorship care. This growing leadership role presents oncology nurses with specific and new educational needs regarding survivorship care.

Basic Mechanisms of Glioblastoma Multiforme Cell Invasion: A Review Article

Glioblastoma multiforme (GBM) is the most common and lethal primary glial neoplasm. GBM can develop both “de novo” or evolve from a previous astrocytoma, being characterized by high proliferation and infiltration into the surrounding tissue. This invasive behavior is the most contributing factor for the poor prognosis of this cancer, despite the multimodal treatment with surgery, radiotherapy and chemotherapy. Understanding and targeting the molecular mechanisms regulating glioma invasion and progression may help in identifying novel therapeutic targets for GBM treatment. This review will give an overview of some of the signaling pathways that have been shown to positively and negatively regulate GBM invasion, including the Wnt, PI3K/Akt, sonic hedgehog-GLI1 and microRNAs.

Calvarium mass as the first presentation of glioblastoma multiforme: A very rare manifestation of high-grade glioma

Glioblastoma multiforme (GBM) is a high grade glial tumor, primarily located in cerebral hemispheres. The most common clinical presentations are slowly progressive neurological deficit such as motor weakness, seizure, and headaches that last less than three months. Calvarium and extra-axial invasion are very rare and generally occur after a brain biopsy or surgery, or secondary to radiotherapy of primary intra-axial glial tumors. We report a case of GBM with calvarium involvement in a 60-year-old man who presented with a frontal bump and left-sided clumsiness. Imaging studies revealed a tumoral lesion that destroyed the frontal bone with white matter involvement of the frontal lobe and extension into the corpus callosum. Histopathological examination of intra-axial and extra-axial lesions revealed pleomorphic high-grade tumor with large areas of necrosis and hemorrhage. Immunohistochemical (IHC) studies confirmed GBM that spread directly into the dura, galea, and calvarium (positive reaction for GFAP, S-100, CD68, OLIG2, and p53). The patient was treated with radiotherapy (60Gy/30 fractions) and concomitant temozolomide. Unfortunately, the patient died seven months after the initial diagnosis.

Surgically benign recovery and histopathologically malignant transformation of a gliomatosis cerebri after radiotherapy: natural course or an unpredictable desired effect?

Gliomatosis cerebri is a rare primary glial neoplasm of the central nervous system characterized by excessive involvement of the brain tissue. Dispersion and infiltrative growth pattern of this insidious pathology limit the utility of total surgical removal and are underlying causes of its poor prognosis. Furthermore, unresponsiveness of gliomatosis cerebri to radiotherapy and its classification as high grade or type 2 is reportedly associated with poor long-term survival. Contrary to our current knowledge, we report the case of a 54-year-old male who was diagnosed with gliomatosis cerebri. He presented with an exceptional clinical and pathological course and poor prognostic factors but was successfully treated with total surgical resection after radiotherapy. The present case findings indicate the potential utility of surgery, usually underestimated, as a curative treatment for gliomatosis cerebri. Clinicians should be aware of negative predictive factors that may help identify a small subset of patients suitable for total surgical tumor removal, as in the present case.

Blood-brain barrier pericyte importance in malignant gliomas: what we can learn from stroke and Alzheimer's disease.

The pericyte, a constitutive component of the central nervous system, is a poorly understood cell type that envelops the endothelial cell with the intended purpose of regulating vascular flow and endothelial cell permeability. Previous studies of pericyte function have been limited to a small number of disease processes such as ischemic stroke and Alzheimer's disease. Recently, publications have postulated a link between glioma stem cell differentiation and pericyte function. These studies suggest that there may be an important interaction of pericytes with tumor cells and other components of the tumor microenvironment in malignant primary glial neoplasms, most notably glioblastoma. This potential cellular interaction underscores the need to pursue more investigations of pericytes in malignant brain tumor biology. In this review, we summarize the functional roles of pericytes, particularly focusing on changes in pericyte biology during response to immune cells, inflammation, and hypoxic conditions. The information presented is based on the available data from studies of pericyte function in other central nervous system diseases but will serve as a foundation for research investigations to further understand the role of pericytes in malignant gliomas.

The effect of postoperative infection on survival in patients with glioblastoma.

OBJECTIVE Glioblastoma is a primary glial neoplasm with a median survival of approximately 1 year. There are anecdotal reports that postoperative infection may confer a survival advantage in patients with glioblastoma. However, only a few case reports in the literature, along with 2 retrospective cohort studies, show some potential link between infection and prolonged survival in patients with glioblastoma. The objective of this study was to evaluate the effect of postoperative infection in patients with glioblastoma using a large national database. METHODS The linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database was searched to identify patients 66 years of age and older with glioblastoma, with and without infection, from 1997 to 2010. The primary outcome was survival after diagnosis. The statistical analysis was performed with a graphical representation using Kaplan-Meier curves, univariate analysis with the log-rank test, and multivariate analysis with proportional hazards modeling. RESULTS A total of 3784 patients with glioblastoma were identified from the database, and from these, 369 (9.8%) had postoperative infection within 1 month of surgery. In patients with glioblastoma who had an infection within 1 month of surgery, there was no significant difference in survival (median 5 months) compared with patients with no infection (median 6 months; p = 0.17). The study also showed that older age, increased Gagne comorbidity score, and having diabetes may be negatively associated with survival. CONCLUSIONS Infection after craniotomy within 1 month was not associated with a survival benefit in patients with glioblastoma.

Subventricular zone microenvironment protects glioblastoma cells from radiotherapy cytotoxicity: role of the chemokine CXCL12

Glioblastoma (GBM) is the most aggressive primary glial tumor in adults and, notwithstanding all the novel treatment approaches to date developed, the outcome remains frustrating poor (1). Indeed, in most cases GBM rapidly relapses also after aggressive multimodal therapy (surgical resection, followed by radiotherapy with concomitant and adjuvant chemotherapy with temozolomide), and the limited benefit of the available treatments at relapse are not able to improve GBM patients’ median overall survival (OS) beyond 15 months (2).

Clinical, immunohistochemical, and molecular genetic prognostic factors in adult patients with glioblastoma

Glioblastoma is the most common primary malignant glial tumor of the brain in adult patients. to define the prognostic value of isocitrate dehydrogenase-1 (IDH-1) mutation and methylguanine-DNA methyltransferase (MGMT) methylation status in patients with glioblastoma (GB) and to analyze the impact of clinical data (gender, age, and tumor site), histological variants of the tumor structure, and time to development of recurrences on the course of the disease. The investigation enrolled 63 GB patients aged 18 to 71 years who had received combined treatment (surgery, chemo- and radiotherapy) at the N.I. Burdenko Research Institute of Neurosurgery, Ministry of Health of the Russian Federation, in the period 2008 to 2011. The investigators performed a morphological examination of all tumor tissue samples and an immunohistochemical examination using anti-IDH-1 R-132 antibody clone («Dianova», Germany) and defined MGMT methylation status by a polymerase chain reaction using the CpGenome DNA Modification Kit («Chemicon International», USA). The data were statistically processed using a package of Statistica 6.0 programs. Patient age, time to development of recurrent glioblastoma, mutations in the IDH-1 gene and MGMT were found to be prognostic factors for overall survival among adult patients in this category. Analysis of clinical findings and identification of molecular genetic aberrations in the tumor cells will be able to elaborate an individual approach to treating patients with glioblastoma in order to increase their survival rates and to improve quality of life.

Metastatic Glioblastoma: A Case Report and Review of the Literature

Glioblastoma, the most common and aggressive primary glial tumor, has a median survival time of approximately 3 months without medical treatment. Surgical resection, radiotherapy, and chemotherapy are the main methods of treatment and have been shown to increase life expectancy 1 to 2 years. The tumor has an infiltrative growth pattern that distorts the normal anatomy and can extend to distant parts of the brain along white matter tracts. While glioblastoma commonly infiltrates surrounding brain tissue and intracranial metastases to the meninges and spinal cord are frequently reported, extra-cranial metastases are extremely rare. This is most probably due to the lack of lymphatic vessels in the brain and inability of the malignant cells to invade blood vessels. We present a case of a 56- year-old female with a history of right temporal glioblastoma, who was found to have biopsy proven metastases to the lung. The patient presented for a chest x-ray, as part of a requirement for a clinical trial, and was found to have bilateral lung nodules; a subsequent chest computed tomography (CT) scan showed numerous pulmonary nodules and low density lesions in the liver. The patient underwent right thoracoscopic wedge resection. Frozen section and permanent sections were diagnostic of metastatic glioblastoma.

Differentiation between high-grade gliomas and metastatic brain tumors using Diffusion Tensor Imaging metrics

IntroductionThe aim of this work was to differentiate between high-grade gliomas and metastatic brain tumors using diffusion tensor derived metrics in the enhancing tumor and peri-tumoral regions. Patients & methodsProspective study was done on 36 patients with provisional MRI diagnosis of high grade gliomas WHO grade III & IV versus metastatic brain tumors, examination was done on 1.5tesla scanner, patients were divided into two groups based on pathology results, the fraction anisotropy (FA), mean diffusivity (MD), linear coefficient (CL), planer coefficient (CP) and spherical coefficient (CS) were measured in the enhancing tumor parts and immediate peri-tumoral edema and results were compared between the two groups. ResultsValues of FA, CL and CP measured in the peri-tumoral edema were significantly high in the metastatic than primary high malignant glial tumors with high specificity (100%) of the CP and high sensitivity of the CL (76.5%) among the three significant values, and no significant differences in the values of MD and CS. The values of the five metrics measured in the enhancing tumor parts showed no significant differences between the two groups. ConclusionBrain metastasis and high-grade gliomas can be differentiated using DTI derived FA, CL and CP measured in the peri-tumoral region.

NI-63 * GLIOMATOSIS CEREBRI: DIAGNOSIS, MANAGEMENT AND OUTCOMES IN THE LARGEST SERIES FROM A SINGLE EUROPEAN INSTITUTION

BACKGROUND AND PURPOSE: Gliomatosis cerebri (GC) is a rare diffusely infiltrating primary glial neoplasm, which is defined as involving at least three lobes of the brain. There often is a striking discordance between clinical presentation and radiological findings. We reviewed the clinical presentation, radiographic appearance and outcome measures from a large single institution series of pathologically defined gliomatosis cerebri cases. METHODS: Between 1992 and 2014, 46 histologically proven cases with GC were encountered. Demographics, initial clinical presentation incl. Karnofsky index (KPS), imaging findings and treatment regimen were retrospectively reviewed and analyzed. RESULTS: Of 46 patients, only eleven were female (23.9%). Mean age at diagnosis was 50.7 years. Most frequent clinical signs were headaches, seizures and mental status changes. CT imaging revealed hypoattenuation of the involved brain parenchyma in 42 of the 46 cases (91.3%) and isodense parenchyma in 4 cases. Magnetic resonance imaging (MRI) generally showed T1-weighted hypointensity and T2-weighted hyperintensity. Frequently bilateral invasion with involvement of the anterior white commissure, the corpus callosum or both was observed. The extent of brain involvement did not demonstrate a significant correlation with overall survival (OS). Lower KPS upon presentation and higher histologic grade did predict shorter OS.

Neuroimaging diagnosis and therapeutic efficacy of different surgical methods of gliomatosis cerebri

To explore the neuroimaging diagnosis and therapeutic efficacy of different surgical methods of gliomatosis cerebri. 26 cases of gliomatosis cerebri at our department between September 2008 and September 2013 were retrospectively analyzed. Preoperative cranial computed tomography (CT), magnetic resonance imaging (MRI) and other multimodal imaging scans were performed. The procedures included stereotactic brain biopsy (n = 11) and large craniotomy lobotomy (n = 15). Whole brain radiotherapy and/or temozolomide therapy was performed postoperatively according to the malignancy of tumors. Follow-ups were conducted to analyze the survival differences between stereotactic brain biopsy and large craniotomy lobotomy groups. According to the different features of multimodal imaging, gliomatosis cerebri could be divided into two types: (1) type I(n = 19) showed a diffuse infiltrating lesion infringing multiple brain lobes or regions with central corpus callosum but without obvious enhancement; (2) type II (n = 7) appeared as sporadic or tuberous enhancement in addition to the features of type I. Pathological diagnosis: pilocytic astrocytoma (n = 2), diffuse astrocytoma (n = 13), oligodendroglial tumors (n = 3), oligoastrocytoma (n = 1), anaplastic astrocytoma (n = 5) and glioblastoma (n = 2). The degree of malignancy was a prognostic factor for postoperative survival in patients with gliomatosis cerebri. The mean survival time (MST) of large craniotomy lobotomy group (23 ± 7) was significantly longer than that of stereotactic brain biopsy group (13 ± 3) (P < 0.05). Gliomatosis cerebri is a primary brain glial tumor with diffuse infiltrative growth but retaining the general structure of central nervous system. Multimodal imaging studies plus pathological examination yield a definitive diagnosis. Comprehensive treatment of operation plus chemo- or radio-therapy can prolong postoperative MST.

Lack of Prognostic Significance of C-erbB-2 Expression in Low- and High- grade Astrocytomas

Astrocytic tumors, the most common primary glial tumors of the central nervous system, are classified from low to high grade according to the degree of anaplasia and presence of necrosis. Despite advances in therapeutic management of high grade astrocytic tumors, prognosis remains poor. In the present study, the frequency and prognostic significance of c-erb-B2 in astrocytic tumors was investigated. Records of 72 patients with low- and high-grade astrocytic tumors were evaluated. The expression of C-erbB-2 was determined immunohistochemically and intensity was recorded as 0 to 3+. Tumors with weak staining (1+) or no staining (0) were considered Her-2 negative, while tumors with moderate (2+) and strong (3+) staining were considered Her-2 positive. Of the 72 patients, 41 (56.9%) had glioblastoma (GBM), 10 (13.9%) had diffuse astrocytoma, 15 (20.8%) had anaplastic astrocytoma, 6 (8.3%) had pilocytic astrocytoma. C-erbB-2 overexpression was detected in the tumor specimens of 17 patients (23.6%). Six (8.3%) tumors, all GBMs, exhibited strong staining, 2 (2.7%) specimens, both GBMs, exhibited moderate staining, and 9 specimens, 5 of them GBMs (12.5%), exhibited weak staining. No staining was observed in diffuse astrocytoma and pilocytic astrocytoma specimens. Median overall survival of patients with C-erbB-2 negative and C-erbB-2 positive tumors were 30 months (95%CI: 22.5-37.4 months) and 16.9 months (95%CI: 4.3-29.5 months), respectively (p=0.244). Although there was no difference in survival, C-erbB-2 overexpression was observed only in the GBM subtype.

Down-modulation of SEL1L, an Unfolded Protein Response and Endoplasmic Reticulum-associated Degradation Protein, Sensitizes Glioma Stem Cells to the Cytotoxic Effect of Valproic Acid

Valproic acid (VPA), an histone deacetylase inhibitor, is emerging as a promising therapeutic agent for the treatments of gliomas by virtue of its ability to reactivate the expression of epigenetically silenced genes. VPA induces the unfolded protein response (UPR), an adaptive pathway displaying a dichotomic yin yang characteristic; it initially contributes in safeguarding the malignant cell survival, whereas long-lasting activation favors a proapoptotic response. By triggering UPR, VPA might tip the balance between cellular adaptation and programmed cell death via the deregulation of protein homeostasis and induction of proteotoxicity. Here we aimed to investigate the impact of proteostasis on glioma stem cells (GSC) using VPA treatment combined with subversion of SEL1L, a crucial protein involved in homeostatic pathways, cancer aggressiveness, and stem cell state maintenance. We investigated the global expression of GSC lines untreated and treated with VPA, SEL1L interference, and GSC line response to VPA treatment by analyzing cell viability via MTT assay, neurosphere formation, and endoplasmic reticulum stress/UPR-responsive proteins. Moreover, SEL1L immunohistochemistry was performed on primary glial tumors. The results show that (i) VPA affects GSC lines viability and anchorage-dependent growth by inducing differentiative programs and cell cycle progression, (ii) SEL1L down-modulation synergy enhances VPA cytotoxic effects by influencing GSCs proliferation and self-renewal properties, and (iii) SEL1L expression is indicative of glioma proliferation rate, malignancy, and endoplasmic reticulum stress statuses. Targeting the proteostasis network in association to VPA treatment may provide an alternative approach to deplete GSC and improve glioma treatments.

Neuroimaging findings of the post-treatment effects of radiation and chemotherapy of malignant primary glial neoplasms.

Post-treatment radiation and chemotherapy of malignant primary glial neoplasms present a wide spectrum of tumor appearances and treatment-related entities. Radiologic findings of these post-treatment effects overlap, making it difficult to distinguish treatment response and failure. The purposes of this article are to illustrate and contrast the imaging appearances of recurrent tumor from necrosis and to discuss other radiologic effects of cancer treatments. It is critical for radiologists to recognize these treatment-related effects to help direct clinical management.

Response to "Reply to [18F]-fluoro-ethyl-L-tyrosine PET: a valuable diagnostic tool in neuro-oncology, but not all that glitters is glioma" by Hutterer et al.

Response to "Reply to [18F]-fluoro-ethyl-L-tyrosine PET: a valuable diagnostic tool in neuro-oncology, but not all that glitters is glioma" by Hutterer et al.

Thrombin-cleaved Fragments of Osteopontin Are Overexpressed in Malignant Glial Tumors and Provide a Molecular Niche with Survival Advantage

Osteopontin (OPN), which is highly expressed in malignant glioblastoma (GBM), possesses inflammatory activity modulated by proteolytic cleavage by thrombin and plasma carboxypeptidase B2 (CPB2) at a highly conserved cleavage site. Full-length OPN (OPN-FL) was elevated in cerebrospinal fluid (CSF) samples from all cancer patients compared with noncancer patients. However, thrombin-cleaved OPN (OPN-R) and thrombin/CPB2-double-cleaved OPN (OPN-L) levels were markedly increased in GBM and non-GBM gliomas compared with systemic cancer and noncancer patients. Cleaved OPN constituted ∼23 and ∼31% of the total OPN in the GBM and non-GBM CSF samples, respectively. OPN-R was also elevated in GBM tissues. Thrombin-antithrombin levels were highly correlated with cleaved OPN, but not OPN-FL, suggesting that the cleaved OPN fragments resulted from increased thrombin and CPB2 in this extracellular compartment. Levels of VEGF and CCL4 were increased in CSF of GBM and correlated with the levels of cleaved OPN. GBM cell lines were more adherent to OPN-R and OPN-L than OPN-FL. Adhesion to OPN altered gene expression, in particular genes involved with cellular processes, cell cycle regulation, death, and inflammation. OPN and its cleaved forms promoted motility of U-87 MG cells and conferred resistance to apoptosis. Although functional mutation of the RGD motif in OPN largely abolished these functions, OPN(RAA)-R regained significant cell binding and signaling function, suggesting that the SVVYGLR motif in OPN-R may substitute for the RGD motif if the latter becomes inaccessible. OPN cleavage contributes to GBM development by allowing more cells to bind in niches where they acquire anti-apoptotic properties.

Recurrent low-grade astroblastoma with signet ring-like cells and high proliferative index

Astroblastoma is a rare primary glial tumor of children and young adults. Radiologically astroblastoma presents as a large well-circumscribed supratentorial, solid-cystic heterogeneous mass. Histology shows perivascular pseudorosettes with hyalinization. Only a single case has been reported with signet-ring-like cell morphology. Signet-ring morphology in primary central nervous system tumors is exceedingly rare. Complete surgical resection is the recommended treatment. Prognosis of astroblastoma depends on the extent of resection and histology. The proliferative index may be a useful tool to define prognosis. We present a case of 10-year-old girl having recurrent low-grade astroblastoma with signet ring-like cells and high proliferative index.

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.