Multimodal assessment shows a mostly preserved cognitive status in incidentally discovered low grade gliomas: A single institution study

Incidentally discovered low-grade gliomas (iLGGs) are poorly reported in the literature. Still less is known about iLGG patients\u2019 neuropsychological profile: It is unclear whether iLGG patients are cognitively proficient, thus further confirming the concept of asymptomatic. From our monoinstitutional cohort of 332 patients operated for LGG from 2000 to 2017 we selected those who underwent a neuropsychological testing (n = 217, from 2008 to 2017), and identified 24 young (mean age 38.5 \ub1 1.06) patients with iLGGs (16 of 24, left hemisphere iLGGs, 8 of 24 right hemisphere iLGGs). The maximum lesions overlap occurred in the left inferior frontal gyrus and in the right anterior cingulate/superior medial frontal gyrus. Patients were cognitively preserved except mild to borderline difficulties in a few of them. The analysis of the equivalent scores (a score laying below or equal to the external nonparametric tolerance limit of adjusted scores corresponding to 0, 1, 2 and 3 are intermediate) highlighted the presence of additional borderline performances. Molecular class correlated with a normal function at visual\u2013spatial intelligence (p = 0.05) and at spatial short-term memory (p = 0.029). Results indicate that at this time of tumor growth, patients\u2019 cognitive abilities are still functional, but are slowly approaching the borderline level

Glioma Associated Stem Cells (GASCs) Isolation and Culture.

Glioma Associated Stem Cells (GASCs) represent a population of nontumorigenic multipotent stem cells hosted in the microenvironment of human gliomas. In vitro, these cells are able, through the release of exosomes, to increase the biological aggressiveness of glioma-initiating cells. The clinical importance of this finding is supported by the strong prognostic value associated with the GASCs surface immunophenotype thus suggesting that this patient-based approach can provide a groundbreaking method to predict prognosis and to exploit novel strategies that target the tumor strom

Cognitive functions in repeated glioma surgery

Low-grade gliomas (LGG) are slow-growing brain tumors infiltrating the central nervous system which tend to recur, often with malignant degeneration after primary treatment. Re-operations are not always recommended due to an assumed higher risk of neurological and cognitive deficits. However, this assumption is relatively ungrounded due to a lack of extensive neuropsychological testing. We retrospectively examined a series of 40 patients with recurrent glioma in eloquent areas of the left hemisphere, who all completed comprehensive pre- (T3) and post-surgical (T4) neuropsychological assessments after a second surgery (4-month follow up). The lesions were most frequent in the left insular cortex and the inferior frontal gyrus. Among this series, in 17 patients the cognitive outcomes were compared before the first surgery (T1), 4 months after the first surgery (T2), and at T3 and T4. There was no significant difference either in the number of patients scoring within the normal range between T3 and T4, or in their level of performance. Further addressing the T1\u2013T4 evolution, there was no significant difference in the number of patients scoring within the normal range. As to their level of performance, the only significant change was in phonological fluency. This longitudinal follow-up study showed that repeated glioma surgery is possible without major damage to cognitive functions in the short-term period (4 months) after surgery

Pre- and Post-surgical Poor Seizure Control as Hallmark of Malignant Progression in Patients With Glioma?

BackgroundRegarding brain tumor-related epilepsy (BTRE), there is an increasing number of evidence about a relationship between epileptogenesis and oncogenesis. A recent study suggests a role of post-surgery seizure outcome on the survival of patients with low-grade glioma (LGG), underlying the need for a targeted and aggressive epilepsy treatment. ObjectiveThis study aims at investigating the possible correlation between pre- and post-surgical seizure control and tumor progression in patients who underwent surgery for LGG. MethodsWe performed a retrospective analysis of patients affected by LGGs and BTRE, in a single high-volume neurosurgical center. Seizure control was assessed before surgery and at 3 years of follow-up. Patients with histological progression in high-grade glioma (HGG) have been evaluated. Clinical features, pre-surgical electroencephalograms (EEGs), and electrocorticography (ECoG) have been analyzed. ResultsAmong 154 subjects, we collected 32 patients who presented a tumor progression in HGG during the follow-up period. The majority had poor seizure control both pre- and post-surgery, never being in Engel class Ia throughout the whole history of their disease. Almost all patients with poor seizure control had pathological ECoG recording. Clinical features of seizures did not correlate with seizure outcome. On the univariate analysis, the age, the post-operative Engel class, and the extent of resection (EOR) were the prognostic factors significantly associated with oncological outcome; nevertheless, on multivariate analysis, Engel class significance was not confirmed, and the only predicting factor were age and EOR. ConclusionsAlthough not confirmed on multivariate analysis, post-surgical seizure control could be a relevant factor to consider during follow-up of BRTE, in particular, when gross total resection is not achieved. Pathological findings on the ECoG may suggest a "hidden" propensity to malignant progression, strictly related to the persistent neuronal hyper-excitability. Further studies with longer follow-up period are needed to confirm our observations

Role of Microenvironment in Glioma Invasion. What We Learned from In Vitro Models

The invasion properties of glioblastoma hamper a radical surgery and are responsible for its recurrence. Understanding the invasion mechanisms is thus critical to devise new therapeutic strategies. Therefore, the creation of in vitro models that enable these mechanisms to be studied represents a crucial step. Since in vitro models represent an over-simplification of the in vivo system, in these years it has been attempted to increase the level of complexity of in vitro assays to create models that could better mimic the behaviour of the cells in vivo. These levels of complexity involved: 1. The dimension of the system, moving from two-dimensional to three-dimensional models; 2. The use of microfluidic systems; 3. The use of mixed cultures of tumour cells and cells of the tumour micro-environment in order to mimic the complex cross-talk between tumour cells and their micro-environment; 4. And the source of cells used in an attempt to move from commercial lines to patient-based models. In this review, we will summarize the evidence obtained exploring these different levels of complexity and highlighting advantages and limitations of each system used

Topoisomerase II beta mediates the resistance of glioblastoma stem cells to replication stress-inducing drugs

Background: Glioblastoma stem cells (GSC) have been extensively recognized as a plausible cause of glioblastoma resistance to therapy and recurrence resulting in high glioblastoma mortality. Abnormalities in the DNA repair pathways might be responsible for the inability of the currently used chemotherapeutics to eliminate the (GSC) subpopulation. Methods: In this work, we compared the expression of sixty DNA repair related genes between primary glioblastoma cell cultures and the glioblastoma enriched stem cell primary cultures. MTT test was used to analyze the effect of selected drugs and immunofluorescence to evaluate the load of DNA damage. Results: We found several differentially expressed genes and we identified topoisomerase II beta (Top2 beta) as the gene with highest up-regulation in GSC. Also among the tested cell lines the expression of Top2 beta was the highest in NCH421k cells, a well-characterized glioblastoma cell line with all the stemness characteristics. On the other hand, Top2 beta expression markedly decreased upon the induction of differentiation by all trans-retinoic acid. Depletion of Top2 beta increased the sensitivity of NCH421k cells to replication stress inducing drugs, such as cisplatin, methyl-methanesulfonate, hydrogen peroxide, and temozolomide. Consistently, we found an increased load of DNA damage and increased Chk1 activation upon Top2 beta depletion in NCH421k cells. Conclusion: We suggest that Top2 beta may represent a new target for gene therapy in glioblastoma. In addition, the other genes that we found to be up-regulated in GSC versus glioblastoma primary cells should be further investigated as glioblastoma theranostics

Carmustine Wafers Implantation in Patients With Newly Diagnosed High Grade Glioma: Is It Still an Option?

Background: The implantation protocol for Carmustine Wafers (CWs) in high grade glioma (HGG) was developed to offer a bridge between surgical resection and adjuvant treatments, such as radio- and chemotherapy. In the last years, however, a widespread use of CWs has been limited due to uncertainties regarding efficacy, in addition to increased risk of infection and elevated costs of treatment. Objective: The aims of our study were to investigate the epidemiology of patients that underwent surgery for HGG with CW implantation, in addition to the assessment of related complications, long-term overall survival (OS), and associated prognostic factors. Methods: Three different medical databases were screened for conducting a systematic review of the literature, according to the PRISMA statement guidelines, evaluating the role of BCNU wafer implantation in patients with newly diagnosed HGG. The search query was based on a combination of medical subject headings (MeSH): “high grade glioma” [MeSH] AND “Carmustine” [MeSH] and free text terms: “surgery” OR “BCNU wafer” OR “Gliadel” OR “systemic treatment options” OR “overall survival.” Results: The analysis of the meta-data demonstrated that there was a significant advantage in using CWs in newly diagnosed GBM in terms of OS, and a very low heterogeneity among the included studies [mean difference 2.64 (95% CI 0.85, 4.44); p = 0.004; I2149 = 0%]. Conversely, no significant difference between the two treatment groups in terms of PFS wad detected (p = 0.55). The analysis of complications showed a relatively higher rate in Carmustine implanted patients, although this difference was not significant (p = 0.53). Conclusions: This meta-analysis seems to suggest that CWs implantation plays a significant role in improving the OS, when used in patients with newly diagnosed HGG. To minimize the risk of side effects, however, a carful patient selection based mainly on patient age and tumor volume should be desirable

Predictors of postoperative seizure outcome in low grade glioma: From volumetric analysis to molecular stratification

The importance of the extent of resection (EOR) has been widely demonstrated as the main predictor for survival, nevertheless its effect on tumor related epilepsy is less investigated. A total of 155 patients were enrolled after a first-line surgery for supratentorial Diffuse Low Grade Gliomas (DLGGs). Postoperative seizure outcome was analyzed stratifying the results by tumor volumetric data and molecular markers according to 2016 WHO classification. Receiver operating characteristic (ROC) curves were computed to asses EOR, residual tumor volume, and 06T2T1 MRI index (expressing the tumor growing pattern) corresponding to optimal seizure outcome. A total of 70.97% of patients were seizure-free 18 months after surgery. Better seizure outcome was observed in IDH1/2 mutated and 1p/19q codeleted subgroup. At multivariate analysis, age (p = 0.014), EOR (p = 0.030), 06T2T1 MRI index (p = 0.016) resulted as independent predictors of postoperative seizure control. Optimal parameters to improve postoperative seizure outcome were EOR 65 85%, 06T2T1 MRI index 64 18 cm3, residual tumor volume 64 15 cm3. This study confirms the role of EOR and tumor growing pattern on postoperative seizure outcome independently from the molecular class. Higher 06T2T1 MRI index, representing the infiltrative component of the tumor, is associated with worse seizure outcome and strengthens the evidence of common pathogenic mechanisms underlying tumor growth and postoperative seizure outcome

Systemic T Cells Immunosuppression of Glioma Stem Cell-Derived Exosomes Is Mediated by Monocytic Myeloid-Derived Suppressor Cells

A major contributing factor to glioma development and progression is its ability to evade the immune system. Nano-meter sized vesicles, exosomes, secreted by glioma-stem cells (GSC) can act as mediators of intercellular communication to promote tumor immune escape. Here, we investigated the immunomodulatory properties of GCS-derived exosomes on different peripheral immune cell populations. Healthy donor peripheral blood mononuclear cells (PBMCs) stimulated with anti-CD3, anti-CD28 and IL-2, were treated with GSC-derived exosomes. Phenotypic characterization, cell proliferation, Th1/Th2 cytokine secretion and intracellular cytokine production were analysed by distinguishing among effector T cells, regulatory T cells and monocytes. In unfractionated PBMCs, GSC-derived exosomes inhibited T cell activation (CD25 and CD69 expression), proliferation and Th1 cytokine production, and did not affect cell viability or regulatory T-cell suppression ability. Furthermore, exosomes were able to enhance proliferation of purified CD4+ T cells. In PBMCs culture, glioma-derived exosomes directly promoted IL-10 and arginase-1 production and downregulation of HLA-DR by unstimulated CD14+ monocytic cells, that displayed an immunophenotype resembling that of monocytic myeloid-derived suppressor cells (Mo-MDSCs). Importantly, the removal of CD14+ monocytic cell fraction from PBMCs restored T-cell proliferation. The same results were observed with exosomes purified from plasma of glioblastoma patients. Our results indicate that glioma-derived exosomes suppress T-cell immune response by acting on monocyte maturation rather than on direct interaction with T cells. Selective targeting of Mo-MDSC to treat glioma should be considered with regard to how immune cells allow the acquirement of effector functions and therefore counteracting tumor progression