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

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

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

Investigation of adhesion and mechanical properties of human glioma cells by single cell force spectroscopy and atomic force microscopy.

Active cell migration and invasion is a peculiar feature of glioma that makes this tumor able to rapidly infiltrate into the surrounding brain tissue. In our recent work, we identified a novel class of glioma-associated-stem cells (defined as GASC for high-grade glioma--HG--and Gasc for low-grade glioma--LG) that, although not tumorigenic, act supporting the biological aggressiveness of glioma-initiating stem cells (defined as GSC for HG and Gsc for LG) favoring also their motility. Migrating cancer cells undergo considerable molecular and cellular changes by remodeling their cytoskeleton and cell interactions with surrounding environment. To get a better understanding about the role of the glioma-associated-stem cells in tumor progression, cell deformability and interactions between glioma-initiating stem cells and glioma-associated-stem cells were investigated. Adhesion of HG/LG-cancer cells on HG/LG-glioma-associated stem cells was studied by time-lapse microscopy, while cell deformability and cell-cell adhesion strengths were quantified by indentation measurements by atomic force microscopy and single cell force spectroscopy. Our results demonstrate that for both HG and LG glioma, cancer-initiating-stem cells are softer than glioma-associated-stem cells, in agreement with their neoplastic features. The adhesion strength of GSC on GASC appears to be significantly lower than that observed for Gsc on Gasc. Whereas, GSC spread and firmly adhere on Gasc with an adhesion strength increased as compared to that obtained on GASC. These findings highlight that the grade of glioma-associated-stem cells plays an important role in modulating cancer cell adhesion, which could affect glioma cell migration, invasion and thus cancer aggressiveness. Moreover this work provides evidence about the importance of investigating cell adhesion and elasticity for new developments in disease diagnostics and therapeutics

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

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

Risk Assessment by Pre-surgical Tractography in Left Hemisphere Low-Grade Gliomas

Background: Tracking the white matter principal tracts is routinely typically included during the pre-surgery planning examinations and has revealed to limit functional resection of low-grade gliomas (LGGs) in eloquent areas. Objective: We examined the integrity of the Superior Longitudinal Fasciculus (SLF) and Inferior Fronto-Occipital Fasciculus (IFOF), both known to be part of the language-related network in patients with LGGs involving the temporo-insular cortex. In a comparative approach, we contrasted the main quantitative fiber tracking values in the tumoral (T) and healthy (H) hemispheres to test whether or not this ratio could discriminate amongst patients with different post-operative outcomes. Methods: Twenty-six patients with LGGs were included. We obtained quantitative fiber tracking values in the tumoral and healthy hemispheres and calculated the ratio (HIFOF\u2013TIFOF)/HIFOF and the ratio (HSLF\u2013TSLF)/HSLF on the number of streamlines. We analyzed how these values varied between patients with and without post-operative neurological outcomes and between patients with different post-operative Engel classes. Results: The ratio for both IFOF and SLF significantly differed between patient with and without post-operative neurological language deficits. No associations were found between white matter structural changes and post-operative seizure outcomes. Conclusions: Calculating the ratio on the number of streamlines and fractional anisotropy between the tumoral and the healthy hemispheres resulted to be a useful approach, which can prove to be useful during the pre-operative planning examination, as it gives a glimpse on the potential clinical outcomes in patients with LGGs involving the left temporo-insular cortex

Article a new epigenetic model to stratify glioma patients according to their immunosuppressive state

Gliomas are the most common primary neoplasm of the central nervous system. A promising frontier in the definition of glioma prognosis and treatment is represented by epigenetics. Further-more, in this study, we developed a machine learning classification model based on epigenetic data (CpG probes) to separate patients according to their state of immunosuppression. We considered 573 cases of low-grade glioma (LGG) and glioblastoma (GBM) from The Cancer Genome Atlas (TCGA). First, from gene expression data, we derived a novel binary indicator to flag patients with a favorable immune state. Then, based on previous studies, we selected the genes related to the immune state of tumor microenvironment. After, we improved the selection with a data-driven procedure, based on Boruta. Finally, we tuned, trained, and evaluated both random forest and neural network classifiers on the resulting dataset. We found that a multi-layer perceptron network fed by the 338 probes selected by applying both expert choice and Boruta results in the best performance, achieving an out-of-sample accuracy of 82.8%, a Matthews correlation coefficient of 0.657, and an area under the ROC curve of 0.9. Based on the proposed model, we provided a method to stratify glioma patients according to their epigenomic state

Mismatch-repair protein expression in high-grade gliomas: A large retrospective multicenter study

Background: DNA mismatch repair (MMR) is a system for repairing errors in DNA replication. Cancer cells with MMR deficiency can have immunohistochemical loss of MMR protein expression leading to a hypermutable phenotype that may correlate with anti-PD1 efficacy. Scant data exist about immunohistochemical loss of MMR protein expression in high-grade gliomas (HGG). Materials and Methods: We performed a large multicenter retrospective study to investigate the frequency and the prognostic role of immunohistochemical loss of MMR protein expression in HGG patients; we nevertheless evaluated the association between this status and clinical or molecular characteristics. Immunohistochemical loss of MMR protein expression was recorded as partial or complete loss of at least 1 MMR protein. Results: We analyzed the expression of MMR proteins in tumor tissue of 355 consecutive patients. Partial and complete immunohistochemical loss of MMR proteins was found in 43/355 samples (12.1%) and among these, 15 cases (4.2%) showed a complete loss of at the least one MMR protein. Alteration of MSH2 expression was found in 55.8%, MSH6 in 46.5%, PMS2 in 34.9%, and MLH1 in 30.2%. Alteration of MMR protein expression was statistically more frequent in anaplastic gliomas, in recurrent disease, in patients treated with temozolomide, and in IDH-mut gliomas. Immunohistochemical loss of MMR proteins was not associated with survival, adjusting for clinically relevant confounders. Conclusions: MMR protein expression status did not affect survival in HGG patients. We identified clinical and molecular characteristics correlating with immunohistochemical loss of MMR proteins expression. A large study should be performed to analyze its predictive role of immune checkpoint inhibitor efficacy in these subgroups of patients