Speed-accuracy strategy regulations in prefrontal tumor patients

The ability to flexibly switch between fast and accurate decisions is crucial in everyday life. Recent neuroimaging evidence suggested that left lateral prefrontal cortex plays a role in switching from a quick response strategy to an accurate one. However, the causal role of the left prefrontal cortex in this particular, non-verbal, strategy switch has never been demonstrated. To fill this gap, we administered a perceptual decision-making task to neuro-oncological prefrontal patients, in which the requirement to be quick or accurate changed randomly on a trial-by-trial basis. To directly assess hemispheric asymmetries in speed-accuracy regulation, patients were tested a few days before and a few days after surgical excision of a brain tumor involving either the left (N=13) or the right (N=12) lateral frontal brain region. A group of age- and education-matched healthy controls was also recruited. To gain more insight on the component processes implied in the task, performance data (accuracy and speed) were not only analyzed separately but also submitted to a diffusion model analysis. The main findings indicated that the left prefrontal patients were impaired in appropriately adopting stricter response criteria in speed-to-accuracy switching trials with respect to healthy controls and right prefrontal patients, who were not impaired in this condition. This study demonstrates that the prefrontal cortex in the left hemisphere is necessary for flexible behavioral regulations, in particular when setting stricter response criteria is required in order to successfully switch from a speedy strategy to an accurate one

Acute effects of surgery on emotion and personality of brain tumor patients: Surgery impact, histological aspects, and recovery

Background. Cognitive effects of brain surgery for the removal of intracranial tumors are still under investigation. For many basic sensory/motor or language-based functions, focal, albeit transient, cognitive deficits have been reported low-grade gliomas (LGGs); however, the effects of surgery on higher-level cognitive functions are still largely unknown. It has recently been shown that, following brain tumors, damage to different brain regions causes a variety of deficits at different levels in the perception and interpretation of emotions and intentions. However, the effects of different tumor histologies and, more importantly, the effects of surgery on these functions have not been examined. Methods. The performance of 66 patients affected by high-grade glioma (HGG), LGG, and meningioma on 4 tasks tapping different levels of perception and interpretations of emotion and intentions was assessed before, immediately after, and (for LGG patients) 4 months following surgery. Results. Results showed that HGG patients were generally already impaired in the more perceptual tasks before surgery and did not show surgery effects. Conversely, LGG patients, who were unimpaired before surgery, showed a significant deficit in perceptual tasks immediately after surgery that was recovered within few months. Meningioma patients were substantially unimpaired in all tasks. Conclusions. These results show that surgery can be relatively safe for LGG patients with regard to the higher-level, more complex cognitive functions and can provide further useful information to the neurosurgeon and improve communication with both the patient and the relatives about possible changes that can occur immediately after surgery

Brain Mapping: Real-Time Neuropsychological Testing Experience during Low-Grade Tumor Resection

ABSTRACT Awake surgery and direct electrical stimulation are performed to maximize the extent of resection while minimizing the risk of neurological and cognitive deficits. Direct electrical stimulation is a highly reliable method for monitoring simple brain functions when stimulating the sensorimotor cortex, or areas involved in speech articulation; however, negative mapping increases when testing higher functions related to language or cognition. By using DES alone, when resection involves areas supporting higher level cognition, the surgeon may receive poor feedback on the patient's cognitive status. To collect more information on the patient's cognitive status during resection, we developed real-time neuropsychological testing, an intensive neuropsychological monitoring method which is performed in addition to direct electrical stimulation. The technique includes a large number of tests that are administered in a continuously rotating and repeating pattern at different stages per anatomical area. The aim is to have a continuous feedback on the patient's cognitive status by reducing the risk of negative mapping. This chapter discusses this novel real-time neuropsychological test and presents the cognitive functional dynamics during surgery and recovery brought to light by the testing

Identification of a Prognostic Microenvironment-Related Gene Signature in Glioblastoma Patients Treated with Carmustine Wafers

SIMPLE SUMMARY: Carmustine wafer (CW) implantation into the resection cavity of patients operated for glioblastoma (GBM) was approved as an adjuvant treatment before the Stupp Protocol. Although contrasting clinical results limited its use, our retrospective study on 116 GBM treated with CW showed a significant benefit in terms of OS in a subgroup of patients. Since GBM growth, progression, and drug resistance are supported by the surrounding environment, and since the tumor microenvironment (TME) is the source of druggable targets, we hypothesized that the TME of patients who benefited from CW could have different characteristics compared to patients who did not show any advantage. Exploiting a human in vitro model of glioma microenvironment and a transcriptomic approach, we found a different gene signature suggesting the importance of developing in vitro models that mimic the properties of human cancers and that can help to study individual patient characteristics at the cellular and molecular level. ABSTRACT: Despite the state-of-the-art treatment, patients diagnosed with glioblastoma (GBM) have a median overall survival (OS) of 14 months. The insertion of carmustine wafers (CWs) into the resection cavity as adjuvant treatment represents a promising option, although its use has been limited due to contrasting clinical results. Our retrospective evaluation of CW efficacy showed a significant improvement in terms of OS in a subgroup of patients. Given the crucial role of the tumor microenvironment (TME) in GBM progression and response to therapy, we hypothesized that the TME of patients who benefited from CW could have different properties compared to that of patients who did not show any advantage. Using an in vitro model of the glioma microenvironment, represented by glioma-associated-stem cells (GASC), we performed a transcriptomic analysis of GASC isolated from tumors of patients responsive and not responsive to CW to identify differentially expressed genes. We found different transcriptomic profiles, and we identified four genes, specifically down-regulated in GASC isolated from long-term survivors, correlated with clinical data deposited in the TCGA–GBM dataset. Our results highlight that studying the in vitro properties of patient-specific glioma microenvironments can help to identify molecular determinants potentially prognostic for patients treated with CW

recovering and worsening at design fluency in 22 neurosurgical patients preimmediately post surgery and follow up testing

The five-point test (FPT) measures the ability to voluntarily generate non-verbal novel patterns. We investigated how this ability can be impaired or improved before immediately after brain surgery, and at follow-up. Twenty-two patients undergoing neurosurgery in the right hemisphere performed the FPT at T0 (pre-), T1 (1 week post-), and T2 (follow-up at 5 months after surgery). Significant improvements at T1 (in patients who had a deficit at T0) measured recovering (N=3/22); in addition there were patients who become pathological (8/22) and subjects who presented with the same degree of impairment as observed at T0 (stable, 1/22). Similarly, at T2 (4-5 months after surgery) we measured the effect of post-op reorganization: there were patients (5/22) who had been pathological at T1 and recovered at T2. Lesions overlapped in the right body of the corpus callosum/anterior cingulum reflecting the overcome of the deficit. Amelioration can be an effect of edema reduction. In addition, there were those who become pathological (4/22). Lesions overlapped in the right supramarginal gyrus. Lastly, there were subjects who presented with the same degree of impairment as observed at T1 (stable, 4/22) and those who remained spared (9/22). Multiple regression analysis was used to test if the number of strategies (CSs) used to solve the task or the perseverative behaviour (ErrI) significantly predicted participants' stratification, namely patients who worsened those who improved and patients who remained spared. It was found that the use of strategies significantly predicted participants' stratification, whereas perseverative behaviour was not a significant predictor

Identifying environmental sounds: a multimodal mapping study

Our environment is full of auditory events such as warnings or hazards, and their correct recognition is essential. We explored environmental sound (ES) recognition in a series of studies. In study 1 we performed an Activation Likelihood Estimation (ALE) meta-Analysis of neuroimaging studies addressing ES processing to delineate the network of areas consistently involved in ES processing. In study 2 we reported a series of 7 neurosurgical patients with lesions involving the areas found consistently activated by the ALE meta-analysis and tested their ES recognition abilities. In study 3 we investigated how the areas involved in ES might be functionally deregulated as an effect of lesion by performing an fMRI study on patients (in comparison to healthy controls). Areas found to be consistently activated in the ALE quantitative meta-analysis involved the STG/MTG, insula/rolandic operculum, parahippocampal gyrus and inferior frontal gyrus complex bilaterally. Some of these areas were found modulated by design choices, e.g., type of task, type of control condition, type of stimuli. Patients with lesions in these areas of the left and the right hemisphere had an impaired ES recognition. The most frequently lesioned area corresponded to the hippocampus/insula/superior temporal gyrus. For the most part, the patients’ responses were unrelated to the target sounds or were semantically related to the target sounds. The other type of responses were: auditorily related, semantically and auditorily related, and I don't Know answers. The fMRI evidenced deregulations of the activation reported in the right IFG and in the STG bilaterally and in the left insula. We showed that some of these clusters of activation truly reflect ES processing, whereas others are related to design choices. Our results allowed a parcelization of the activation found along the MTG/STG are

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

The human RECQ1 helicase is highly expressed in glioblastoma and plays an important role in tumor cell proliferation

<p>Abstract</p> <p>Background</p> <p>RecQ helicases play an essential role in the maintenance of genome stability. In humans, loss of RecQ helicase function is linked with predisposition to cancer and/or premature ageing. Current data show that the specific depletion of the human RECQ1 helicase leads to mitotic catastrophe in cancer cells and inhibition of tumor growth in mice.</p> <p>Results</p> <p>Here, we show that RECQ1 is highly expressed in various types of solid tumors. However, only in the case of brain gliomas, the high expression of RECQ1 in glioblastoma tissues is paralleled by a lower expression in the control samples due to the poor expression of RECQ1 in non-dividing tissues. This conclusion is validated by immunohistochemical analysis of a tissue microarray containing 63 primary glioblastomas and 19 perilesional tissue samples, as control. We also show that acute depletion of RECQ1 by RNAi results in a significant reduction of cellular proliferation, perturbation of S-phase progression, and spontaneous γ-H2AX foci formation in T98G and U-87 glioblastoma cells. Moreover, RECQ1 depleted T98G and U-87 cells are hypersensitive to HU or temozolomide treatment.</p> <p>Conclusions</p> <p>Collectively, these results indicate that RECQ1 has a unique and important role in the maintenance of genome integrity. Our results also suggest that RECQ1 might represent a new suitable target for anti cancer therapies aimed to arrest cell proliferation in brain gliomas.</p

Semaphorin-7A on Exosomes: A Promigratory Signal in the Glioma Microenvironment

Exosomes are one of the most important mediators of the cross talk occurring between glioma stem cells (GSCs) and the surrounding microenvironment. We have previously shown that exosomes released by patient-derived glioma-associated stem cells (GASC) are able to increase, in vitro, the aggressiveness of both GSC and glioblastoma cell lines. To understand which molecules are responsible for this tumour-supporting function, we performed a descriptive proteomic analysis of GASC-exosomes and identified, among the others, Semaphorin7A (SEMA7A). SEMA7A was described as a promigratory cue in physiological and pathological conditions, and we hypothesised that it could modulate GSC migratory properties. Here, we described that SEMA7A is exposed on GASC-exosomes' surface and signals to GSC through Integrin \u3b21. This interaction activates focal adhesion kinase into GSC and increases their motility, in our patient-based in vitro model. Our findings suggest SEMA7A-\u3b21-integrin as a new target to disrupt the communication between GSCs and the supporting microenvironment