Tamara Ius

Low-grade glioma surgery in eloquent areas: Volumetric analysis of extent of resection and its impact on overall survival. A single-institution experience in 190 patients - Clinical article

OBJECT A growing number of published studies have recently demonstrated the role of resection in overall survival (OS) for patients with gliomas. In this retrospective study, the authors objectively investigated the role of the extent of resection (EOR) in OS in patients with low-grade gliomas (LGGs). METHODS Between 1998 and 2011, 190 patients underwent surgery for LGGs. All surgical procedures were conducted under corticosubcortical stimulation. The EOR was established by analyzing the pre- and postoperative volumes of the gliomas on T2-weighted MRI studies. The difference between the preoperative tumor volumes was also investigated by measuring the volumetric difference between the T2- and T1-weighted MRI images (ΔVT2T1) to evaluate how the diffusive tumor-growing pattern affected the EOR achieved. RESULTS The median preoperative tumor volume was 55 cm(3), and in almost half of the patients the EOR was greater than 90%. In this study, patients with an EOR of 90% or greater had an estimated 5-year OS rate of 93%, those with EOR between 70% and 89% had a 5-year OS rate of 84%, and those with EOR less than 70% had a 5-year OS rate of 41% (p < 0.001). New postoperative deficits were noted in 43.7% of cases, while permanent deficits occurred in 3.16% of cases. There were 41 deaths (21.6%), and the median follow-up was 4.7 years. A further volumetric analysis was also conducted to compare 2 different intraoperative protocols (Series 1 [intraoperative electrical stimulation alone] vs Series 2 [intraoperative stimulation plus overlap of functional MRI/fiber tracking diffusion tensor imaging data on a neuronavigation system]). Patients in Series 1 had a median EOR of 77%, while those in Series 2 had a median EOR of 90% (p = 0.0001). Multivariate analysis showed that OS is influenced not only by EOR (p = 0.001) but also by age (p = 0.003), histological subtype (p = 0.005), and the ΔVT2T1 value (p < 0.0001). Progression-free survival is similarly influenced by histological subtype (fibrillary astrocytoma, p = 0.003), EOR (p < 0.0001), and ΔVT2T1 value (p < 0.0001), as is malignant progression-free survival (p = 0.003, p < 0.0001, and p < 0.0001, respectively). Finally, the study shows that the higher the ΔVT2T1 value, the less extensive the currently possible resection, highlighting an apparent correlation between the ΔVT2T1 value itself and EOR (p < 0.0001). CONCLUSIONS The EOR and the ΔVT2T1 values are the strongest independent predictors in improving OS as well as in delaying tumor progression and malignant transformation. Furthermore, the ΔVT2T1 value may be useful as a predictive index for EOR. Finally, due to intraoperative corticosubcortical mapping and the overlap of functional data on the neuronavigation system, major resection is possible with an acceptable risk and a significant increase in expected OS.

Surgery of insular nonenhancing gliomas: volumetric analysis of tumoral resection, clinical outcome, and survival in a consecutive series of 66 cases.

BACKGROUND Despite intraoperative technical improvements, the insula remains a challenging area for surgery because of its critical relationships with vascular and neurophysiological functional structures. OBJECTIVE To retrospectively investigate the morbidity profile in insular nonenhancing gliomas, with special emphasis on volumetric analysis of tumoral resection. METHODS From 2000 to 2010, 66 patients underwent surgery. All surgical procedures were conducted under cortical-subcortical stimulation and neurophysiological monitoring. Volumetric scan analysis was applied on T2-weighted magnetic resonance images (MRIs) to establish preoperative and postoperative tumoral volume. RESULTS The median preoperative tumor volume was 108 cm. The median extent of resection was 80%. The median follow-up was 4.3 years. An immediate postoperative worsening was detected in 33.4% of cases; a definitive worsening resulted in 6% of cases. Patients with extent of resection of > 90% had an estimated 5-year overall survival rate of 92%, whereas those with extent of resection between 70% and 90% had a 5-year overall survival rate of 82% (P < .001). The difference between preoperative tumoral volumes on T2-weighted MRI and on postcontrast T1-weighted MRI ([T2 - T1] MRI volume) was computed to evaluate the role of the diffusive tumoral growing pattern on overall survival. Patients with preoperative volumetric difference < 30 cm demonstrated a 5-year overall survival rate of 92%, whereas those with a difference of > 30 cm had a 5-year overall survival rate of 57% (P = .02). CONCLUSION With intraoperative cortico-subcortical mapping and neurophysiological monitoring, a major resection is possible with an acceptable risk and a significant result in the follow-up.

Glioma-Associated Stem Cells: A Novel Class of Tumor-Supporting Cells Able to Predict Prognosis of Human Low-Grade Gliomas

Background: Translational medicine aims at transferring advances in basic science research into new approaches for diagnosis and treatment of diseases. Low‐grade gliomas (LGG) have a heterogeneous clinical behavior that can be only partially predicted employing current state‐of‐the‐art markers, hindering the decision‐making process. To deepen our comprehension on tumor heterogeneity, we dissected the mechanism of interaction between tumor cells and relevant components of the neoplastic environment, isolating, from LGG and high‐grade gliomas (HGG), proliferating stem cell lines from both the glioma stroma and, where possible, the neoplasm. Methods and Findings: We isolated glioma‐associated stem cells (GASC) from LGG (n=40) and HGG (n=73). GASC showed stem cell features, anchorage‐independent growth, and supported the malignant properties of both A172 cells and human glioma‐stem cells, mainly through the release of exosomes. Finally, starting from GASC obtained from HGG (n=13) and LGG (n=12) we defined a score, based on the expression of 9 GASC surface markers, whose prognostic value was assayed on 40 subsequent LGG‐patients. At the multivariate Cox analysis, the GASC‐based score was the only independent predictor of overall survival and malignant progression free‐survival. Conclusions: The microenvironment of both LGG and HGG hosts non‐tumorigenic multipotent stem cells that can increase in vitro the biological aggressiveness of glioma‐initiating cells through the release of exosomes. The clinical importance of this finding is supported by the strong prognostic value associated with the characteristics of GASC. This patient‐based approach can provide a groundbreaking method to predict prognosis and to exploit novel strategies that target the tumor stroma. Stem Cells 2014;32:1239–1253

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

BackgroundRecQ 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.ResultsHere, 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.ConclusionsCollectively, 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.

Smaller, softer, lower-impedance electrodes for human neuroprosthesis: a pragmatic approach

Finding the most appropriate technology for building electrodes to be used for long term implants in humans is a challenging issue. What are the most appropriate technologies? How could one achieve robustness, stability, compatibility, efficacy, and versatility, for both recording and stimulation? There are no easy answers to these questions as even the most fundamental and apparently obvious factors to be taken into account, such as the necessary mechanical, electrical and biological properties, and their interplay, are under debate. We present here our approach along three fundamental parallel pathways: we reduced electrode invasiveness and size without impairing signal-to-noise ratio, we increased electrode active surface area by depositing nanostructured materials, and we protected the brain from direct contact with the electrode without compromising performance. Altogether, these results converge toward high-resolution ECoG arrays that are soft and adaptable to cortical folds, and have been proven to provide high spatial and temporal resolution. This method provides a piece of work which, in our view, makes several steps ahead in bringing such novel devices into clinical settings, opening new avenues in diagnostics of brain diseases, and neuroprosthetic applications.

Surgery for insular low-grade glioma: predictors of postoperative seizure outcome.

OBJECT Although a number of recent studies on the surgical treatment of insular low-grade glioma (LGG) have demonstrated that aggressive resection leads to increased overall patient survival and decreased malignant progression, less attention has been given to the results with respect to tumor-related epilepsy. The aim of this investigation was to evaluate the impact of volumetric, histological, and intraoperative neurophysiological factors on seizure outcome in patients with insular LGG. METHODS The authors evaluated predictors of seizure outcome with special emphasis on both the extent of tumor resection (EOR) and the tumors infiltrative pattern quantified by computing the difference between the preoperative T2- and T1-weighted MR images (ΔVT2T1) in 52 patients with preoperative drug-resistant epilepsy. RESULTS The 12-month postoperative seizure outcome (Engel class) was as follows: seizure free (Class I), 67.31%; rare seizures (Class II), 7.69%; meaningful seizure improvement (Class III), 15.38%; and no improvement or worsening (Class IV), 9.62%. Poor seizure control was more common in patients with a longer preoperative seizure history (p < 0.002) and higher frequency of seizures (p = 0.008). Better seizure control was achieved in cases with EOR ≥ 90% (p < 0.001) and ΔVT2T1 < 30 cm(3) (p < 0.001). In the final model, ΔVT2T1 proved to be the strongest independent predictor of seizure outcome in insular LGG patients (p < 0.0001). CONCLUSIONS No or little postoperative seizure improvement occurs mainly in cases with a prevalent infiltrative tumor growth pattern, expressed by high ΔVT2T1 values, which consequently reflects a smaller EOR.

Foreign accent syndrome: a multimodal mapping study.

The present study explored the functional neuroanatomy of Foreign Accent Syndrome (FAS) in an Italian native speaker who developed an altered speech rhythm and melody following a circumscribed tumour to the left precentral gyrus. Structural, functional, fibre tracking and intraoperative findings were combined. No signs of dysarthria, apraxia of speech, or aphasia nor other cognitive deficits were detected, except for the fact that the patient was perceived as a non-native speaker. The patient fMRI maps were compared with a control group of 12 healthy controls. During counting, sentences and pseudoword pronunciation the patient showed an additional increased sparse activation in areas around the pre/postcentral gyrus corresponding to those involved in phonation (i.e., larynx motor area). The intraoperative cortical stimulation mapping evidenced a mouth motor representation close to the tumour, a motor type of speech arrest site just below it, and anteriorly a proper speech arrest site. Our results are discussed within the current neurolinguistic models of speech production, and emphasize the importance of the primary motor cortex. We argue that this FAS case should be thought of as a disorder of the feedforward control commands, in particular of the articulator velocity and position maps which are hypothesized to lie along the caudoventral portion of the precentral gyrus.

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.

Brain mapping: a novel intraoperative neuropsychological approach.

OBJECTIVE Awake surgery and mapping are performed in patients with low-grade tumors infiltrating functional brain areas for which the greater the resection, the longer the patient survival. However, the extent of resection is subject to preservation of cognitive functions, and in the absence of proper feedback during mapping, the surgeon may be less prone to perform an extensive resection. The object of this study was to perform real-time continuous assessment of cognitive function during the resection of tumor tissue that could infiltrate eloquent tissue. METHODS The authors evaluated the use of new, complex real-time neuropsychological testing (RTNT) in a series of 92 patients. They reported normal scoring and decrements in patient performance as well as reversible intraoperative neuropsychological dysfunctions in tasks (for example, naming) associated with different cognitive abilities. RESULTS RTNT allowed one to obtain a more defined neuropsychological picture of the impact of surgery. The influence of this monitoring on surgical strategy was expressed as the mean extent of resection: 95% (range 73%-100%). At 1 week postsurgery, the neuropsychological scores were very similar to those detected with RTNT, revealing the validity of the RTNT technique as a predictive tool. At the follow-up, the majority of neuropsychological scores were still > 70%, indicating a decrease of < 30%. CONCLUSIONS RTNT enables continuous enriched intraoperative feedback, allowing the surgeon to increase the extent of resection. In sharp contrast to classic mapping techniques, RTNT allows testing of several cognitive functions for one brain area under surgery.

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.