Giorgio Carrabba

Motor and language DTI Fiber Tracking combined with intraoperative subcortical mapping for surgical removal of gliomas

Preoperative DTI Fiber Tracking (DTI-FT) reconstruction of functional tracts combined with intraoperative subcortical mapping (ISM) is potentially useful to improve surgical procedures in gliomas located in eloquent areas. Aims of the study are: (1) to evaluate the modifications of fiber trajectory induced by the tumor; (2) to validate preoperative DTI-FT results with intraoperative identification of functional subcortical sites through direct subcortical stimulation; (3) to evaluate the impact of preoperative DTI-FT reconstructions in a neuronavigational setup combined with ISM technique on duration and modalities of surgical procedures, and on functional outcome of the patients. Data are available on 64 patients (52 low-grade and 12 high-grade gliomas). DTI-FT was acquired by a 3-T MR scanner with a single-shot EPI sequence (TR/TE 8986/80 ms, b=1000 s/mm) with gradients applied along 32 non-collinear directions. 3D Fast Field Echo (FFE) T1-weighted imaging (TR/TE 8/4 ms) was performed for anatomic guidance. The corticospinal tract (CST), superior longitudinal, inferior fronto-occipital and uncinatus fasciculi were reconstructed. Data were transferred to the neuronavigational system. Functional subcortical sites identified during ISM were correlated with fiber tracts depicted by DTI-FT. In high-grade gliomas, DTI-FT depicted tracts mostly at the tumor periphery; in low-grade gliomas, fibers were frequently located inside the tumor mass. There was a high correlation between DTI-FT and ISM (sensitivity for CST=95%, language tracts=97%). For a proper reconstruction of the tracts, it was necessary to use a low FA threshold of fiber tracking algorithm and to position additional regions of interest (ROIs). The combination of DTI-FT and ISM decreased the duration of surgery, patient fatigue, and intraoperative seizures. Combination of DTI-FT and ISM allows accurate identification of eloquent fiber tracts and enhances surgical performance and safety maintaining a high rate of functional preservation.

Intraoperative subcortical language tract mapping guides surgical removal of gliomas involving speech areas

OBJECTIVESubcortical stimulation can be used to identify functional language tracts during resection of gliomas located close to or within language areas or pathways. The objective of the present study was to investigate the feasibility of the routine use of subcortical stimulation for identification of language tracts in a large series of patients with gliomas and to determine the influence that subcortical language tract identification exerted on the extent of surgery and on the appearance of immediate and definitive postoperative deficits. METHODSSubcortical stimulation for language tract identification was systematically used during surgical removal of 88 gliomas (44 high-grade and 44 low-grade gliomas) involving language pathways. Procedures were performed during asleep/awake craniotomy. Subcortical stimulation was continuously alternated with surgical resection in a back-and-forth fashion. Language performances were tested by neuropsychological language evaluation preoperatively and at 3, 30, and 90 days after surgery. RESULTSLanguage tracts were identified in 59% of patients, with differences according to tumor location but not according to histological grade. Language tract identification influenced the ability to reach a complete tumor removal in low-grade gliomas, in which tracts were documented inside the peripheral mass of the tumor. Identification of language tracts was associated with a higher occurrence of transient postoperative deficits (67.3% of cases), but a low occurrence of definitive morbidity (2.3% of cases). A pattern of typical language disturbances related to the phonological and semantic system can be identified according to tumor location, with preservation being important for the maintenance of language integrity. CONCLUSIONOur study supports the routine use of subcortical stimulation for language tract identification as a reliable tool for guiding surgical removal of gliomas in or in close proximity to language areas or pathways.

Tau elevations in the brain extracellular space correlate with reduced amyloid-β levels and predict adverse clinical outcomes after severe traumatic brain injury

Axonal injury is believed to be a major determinant of adverse outcomes following traumatic brain injury. However, it has been difficult to assess acutely the severity of axonal injury in human traumatic brain injury patients. We hypothesized that microdialysis-based measurements of the brain extracellular fluid levels of tau and neurofilament light chain, two low molecular weight axonal proteins, could be helpful in this regard. To test this hypothesis, 100 kDa cut-off microdialysis catheters were placed in 16 patients with severe traumatic brain injury at two neurological/neurosurgical intensive care units. Tau levels in the microdialysis samples were highest early and fell over time in all patients. Initial tau levels were >3-fold higher in patients with microdialysis catheters placed in pericontusional regions than in patients in whom catheters were placed in normal-appearing right frontal lobe tissue (P = 0.005). Tau levels and neurofilament light-chain levels were positively correlated (r = 0.6, P = 0.013). Neurofilament light-chain levels were also higher in patients with pericontusional catheters (P = 0.04). Interestingly, initial tau levels were inversely correlated with initial amyloid-β levels measured in the same samples (r = -0.87, P = 0.000023). This could be due to reduced synaptic activity in areas with substantial axonal injury, as amyloid-β release is closely coupled with synaptic activity. Importantly, high initial tau levels correlated with worse clinical outcomes, as assessed using the Glasgow Outcome Scale 6 months after injury (r = -0.6, P = 0.018). Taken together, our data add support for the hypothesis that axonal injury may be related to long-term impairments following traumatic brain injury. Microdialysis-based measurement of tau levels in the brain extracellular space may be a useful way to assess the severity of axonal injury acutely in the intensive care unit. Further studies with larger numbers of patients will be required to assess the reproducibility of these findings and to determine whether this approach provides added value when combined with clinical and radiological information.

Angiogenesis and Invasion in Gliomas

Angiogenesis and tumor cell invasion are pathophysiological processes playing a pivotal role in glioma development and growth since the earliest phase. Angiogenesis and tumor invasion both can be considered as an invasive process in which cells are activated, and move away from their initial location, by modyfing the adhesiveness with the extracellular matrix, expressing new adhesion molecules, and degrading the extracellular matrix components by the active secretion of proteases. This process requires a complex cross-talking between endothelial and tumor cells, extracellular matrix components, and cellular elements of the host microenviroment. Both processes are under the tight regulation of a balance between stimulating and inhibiting factors. The existence of common mechanisms of regulation and the presence of naturally occurring factors that inihibit angiogenesis and invasion, makes the inhibition of both processes possible. Tumor cells may develop adapting mechanims that can allow the tumor to partially escape to the treatment, particularly when only one mechanism or one process is inhibited. The ideal treatment should simultaneously affect both angiogenesis and invasion, by the isolation or development of novel therapeutics capable of influencing both processes. As their efficacy seems also be dependent on the mode of delivery, additional studies are also needed to improve these modalities, in order to ultimately improve the extent and the duration of the therapeutic response. The most widely used in vitro and in vivo models to study angiogenesis and invasion are also discussed.

Multiinstitutional validation of the University of California at San Francisco low-grade glioma prognostic scoring system: Clinical article

OBJECT Medical and surgical management of low-grade gliomas (LGGs) is complicated by a highly variable clinical course. The authors recently developed a preoperative scoring system to prognosticate outcomes of progression and survival in a cohort of patients treated at a single institution (University of California, San Francisco [UCSF]). The objective of this study was to validate the scoring system in a large patient group drawn from multiple external institutions. METHODS Clinical data from 3 outside institutions (University of Utah, Toronto Western Hospital, and University of California, Los Angeles) were collected for 256 patients (external validation set). Patients were assigned a prognostic score based upon the sum of points assigned to the presence of each of the 4 following factors: 1) location of tumor in presumed eloquent cortex, 2) Karnofsky Performance Scale (KPS) Score <or= 80, 3) age > 50 years, and 4) maximum diameter > 4 cm. A chi-square analysis was used to analyze categorical differences between the institutions; Cox proportional hazard modeling was used to confirm that the individual factors were associated with shorter overall survival (OS) and progression-free survival (PFS); and Kaplan-Meier curves estimated OS and PFS for the score groups. Differences between score groups were analyzed by the log-rank test. RESULTS The median OS duration was 120 months, and there was no significant difference in survival between the institutions. Cox proportional hazard modeling confirmed that the 4 components of the UCSF Low-Grade Glioma Scoring System were associated with lower OS in the external validation set; presumed eloquent location (hazard ratio [HR] 2.04, 95% CI 1.28-2.56), KPS score <or= 80 (HR 5.88, 95% CI 2.44-13.7), age > 50 years (HR 1.82, 95% CI 1.02-3.23), and maximum tumor diameter > 4 cm (HR 2.63, 95% CI 1.58-4.35). The stratification of patients based on scores generated groups (0-4) with statistically different OS and PFS estimates (p < 0.0001, log-rank test). Lastly, the UCSF patient group (construction set) was combined with the external validation set (total of 537 patients) and analyzed for OS and PFS. For all patients, the 5-year survival probability was 0.79; the 5-year cumulative OS probabilities stratified by score group were: score of 0, 0.98; score of 1, 0.90; score of 2, 0.81; score of 3, 0.53; and score of 4, 0.46. CONCLUSIONS The UCSF scoring system accurately predicted OS and PFS in an external large, multiinstitutional population of patients with LGGs. The strengths of this system include ease of use and ability to be applied preoperatively, with the eventual goal of aiding in the design of individualized treatment plans for patients with LGG at diagnosis.

Antiangiogenic therapy by local intracerebral microinfusion improves treatment efficiency and survival in an orthotopic human glioblastoma model.

Targeting active angiogenesis, which is a major hallmark of malignant gliomas, is a potential therapeutic approach. For effective inhibition of tumor-induced neovascularization, antiangiogenic compounds have to be delivered in sufficient quantities over a sustained period of time. The short biological half-life of many antiangiogenic inhibitors and the impaired intratumoral blood flow create logistical difficulties that make it necessary to optimize drug delivery for the treatment of malignant gliomas. In this study, we compared the effects of endostatin delivered by daily systemic administration or local intracerebral microinfusion on established intracranial U87 human glioblastoma xenografts in nude mice. Noninvasive magnetic resonance imaging methods were used to assess treatment effects and additional histopathological analysis of tumor volume, microvessel density, proliferation, and apoptosis rate were performed. Three weeks of local intracerebral microinfusion of endostatin (2 mg/kg/day) led to 74% (P < 0.05) reduction of tumor volumes with decreased microvessel densities (33.5%, P < 0.005) and a 3-fold increased tumor cell apoptosis (P < 0.002). Systemic administration of a 10-fold higher amount of endostatin (20 mg/kg/day) did not result in a reduction of tumor volume nor in an increase of tumor cell apoptosis despite a significant decrease of microvessel densities (26.9%, P < 0.005). Magnetic resonance imaging was used to successfully demonstrate treatment effects. The local microinfusion of human endostatin significantly increased survival when administered at 2 mg/kg/day and was prolonged further when the dose was increased to 12 mg/kg/day. Our results indicate that the local intracerebral microinfusion of antiangiogenic compounds is an effective way to overcome the logistical problems of inhibiting glioma-induced angiogenesis.

Effect of Human Skin-Derived Stem Cells on Vessel Architecture, Tumor Growth, and Tumor Invasion in Brain Tumor Animal Models

Glioblastomas represent an important cause of cancer-related mortality with poor survival. Despite many advances, the mean survival time has not significantly improved in the last decades. New experimental approaches have shown tumor regression after the grafting of neural stem cells and human mesenchymal stem cells into experimental intracranial gliomas of adult rodents. However, the cell source seems to be an important limitation for autologous transplantation in glioblastoma. In the present study, we evaluated the tumor targeting and antitumor activity of human skin-derived stem cells (hSDSCs) in human brain tumor models. The hSDSCs exhibit tumor targeting characteristics in vivo when injected into the controlateral hemisphere or into the tail vein of mice. When implanted directly into glioblastomas, hSDSCs distributed themselves extensively throughout the tumor mass, reduced tumor vessel density, and decreased angiogenic sprouts. In addition, transplanted hSDSCs differentiate into pericyte cell and release high amounts of human transforming growth factor-beta1 with low expression of vascular endothelial growth factor, which may contribute to the decreased tumor cell invasion and number of tumor vessels. In long-term experiments, the hSDSCs were also able to significantly inhibit tumor growth and to prolong animal survival. Similar behavior was seen when hSDSCs were implanted into two different tumor models, the chicken embryo experimental glioma model and the transgenic Tyrp1-Tag mice. Taken together, these data validate the use of hSDSCs for targeting human brain tumors. They may represent therapeutically effective cells for the treatment of intracranial tumors after autologous transplantation.

Combinatorial administration of molecules that simultaneously inhibit angiogenesis and invasion leads to increased therapeutic efficacy in mouse models of malignant glioma.

Purpose: We investigated the ability of the combinatorial administration of different inhibitors with activities on glioma angiogenesis, migration, and proliferation to produce a prolonged inhibition of glioma growth. Experimental Design: We combined inhibitors affecting solely tumor angiogenesis (PF-4/CTF, cyclo-VEGI) or inhibitors affecting both angiogenesis and invasion together (PEX, PF-4/DLR). Results: When administered in combination, these drugs produced a prolonged and increased inhibition of glioma growth independently from the type of inhibitor used. The combinatory administration was more effective than the administration of a single inhibitor alone, and a strong therapeutic response was reached with a significantly lower amount of protein. The strongest inhibition was observed when human PEX and PF-4/DLR, which affect both glioma angiogenesis and invasion by separate mechanisms, were combined. Conclusions: This supports the concept that prolonged glioma growth inhibition can be achieved by simultaneous delivery of molecules that target both tumor and endothelial cells and acting by separate mechanisms.

Subthalamic local field potentials after seven-year deep brain stimulation in Parkinson's disease.

Studies describing subthalamic (STN) local field potentials (LFPs) recorded during deep brain stimulation (DBS) in patients with Parkinsons disease (PD), within the first month after DBS electrode implant, show that DBS modulates specific STN oscillations: whereas low-frequency (LF) oscillations (2-7 Hz) increase, beta oscillations (8-30 Hz) variably decrease. No data show whether LFPs remain stable for longer than one month after DBS surgery. Having long-term information is essential especially for use as a long-term feedback control signal for adaptive DBS systems. To evaluate how STN activity behaves years after prolonged chronic stimulation in PD we studied STN LFPs at rest without DBS and during ongoing DBS, in 11 parkinsonian patients 7 years (7.54±1.04) after STN electrode implantation for DBS (hyperchronic group) and in 16 patients 3 days after STN electrode implantation (acute group). STN LF and beta-band LFPs recorded at rest at 7 years contained almost the same information as those recorded at 3 days. STN recordings showed similar LFP responses to DBS in the acute and hyperchronic stages: whereas during ongoing DBS the LF power band increased for the whole population, beta activity decreased only in nuclei with significant beta activity at baseline. The LF/beta power ratio in all nuclei changed in both study groups, suggesting that this variable might be an even more informative marker of PD than the single LF and beta bands. Because STN LFP activity patterns and STN LFP responses to DBS stay almost unchanged for years after DBS electrode implantation they should provide a consistent feedback control signal for adaptive DBS.

Connectivity constraints on cortical reorganization of neural circuits involved in object naming

The brains plasticity in response to sensory deprivation and other perturbations is well established. While the functional properties of the reorganized areas are under vigorous investigation, the factors that constrain cortical reorganization remain poorly understood. One factor constraining such reorganization may be long-distance subcortical connectivity between relevant cortical regions-reorganization attempts to preserve the functionality of subcortical connections. Here we provide human neurophysiological evidence for the role of the subcortical connections in shaping cortical reorganization of the networks involved in object naming following perturbation of normal function. We used direct electrical stimulation (DES) during surgical removal of gliomas to identify the sites that are involved in naming different categories of objects. The sites that were selectively inhibited in naming either living or non-living objects were displaced relative to those observed with other subject populations, possibly reflecting cortical reorganization due to slowly evolving brain damage. Subcortical DES applied to the white matter underlying these regions also led to category-specific naming deficits. The existence of these subcortical fiber pathways was confirmed using diffusion tensor tractography. These results constitute the first neurophysiological evidence for the critical role of subcortical pathways as part of the neural circuits that are involved in object naming; they also highlight the importance of subcortical connectivity in shaping cortical reorganization following perturbations of normal function.