Surgical Resection Of Gliomas Research Articles

NCMP-20. FACTORS RELATED TO PERMANENT AND TEMPORARY MOTOR DEFICITS IN PATIENTS UNDERGOING GLIOMA RESECTION: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Standard of care treatment for virtually all glioma subtypes starts with maximal safe resection. However, resections that result in motor deficits can negate any survival benefit from surgery and diminish quality of life. Because current evidence on functional outcomes following glioma resection often conflicts and is limited to a small number of case series, retrospective analyses, and reviews, here we performed the first PRISMA-compliant systematic review and meta-analysis of currently published data to identify factors related to permanent and temporary motor deficits after surgery. We searched Ovid Medline, Scopus, Web of Science, CINAHL/EBSCO, PsychInfo, Cochrane and Wiley for studies reporting motor outcomes following surgical resection of glioma. Outcomes were stratified by patient/tumor characteristics, pre-operative condition, and intra-operative factors for both permanent (≥3 months postop) and temporary (<3 months postop) motor deficits. Generalized estimating equations were used to generate odds ratios and 95% confidence intervals. A total of 1,162 titles and abstracts were reviewed for eligibility resulting in the evaluation of 211 full-text articles. Data were extracted from 55 studies including 1,801 patients with 223 (12%) permanent postoperative motor deficits, 428 (24%) temporary motor deficits, and the remaining 1,150 (64%) without motor deficit. Pre-operative deficit was the strongest predictor of permanent post-operative motor deficit (OR 10.56, CI 5.20-21.45, p=7.2E-11), while high pre-operative Karnofsky Performance Scale (KPS) (OR 0.98, CI 0.97-0.99, p=0.036) and subcortical tumor location (OR 0.15, CI 0.025-0.90, p=0.038) were associated with no permanent deficit. Supratotal resection was significantly associated with temporary motor deficits (OR 3.54E+12, CI 3.53+E13-3.56E+17, p<2E-16), and asleep craniotomies were associated with no deficit (OR 1.68E-01, CI 4.93E-02–5.71E-01, p=0.0043). Ultimately, this study represents the largest analysis of motor outcome data in glioma surgery to date.

Targeting Catechol-O-Methyltransferase Induces Mitochondrial Dysfunction and Enhances the Efficacy of Radiotherapy in Glioma.

Radiotherapy (RT) is commonly used to try to eliminate any remaining tumor cells following surgical resection of glioma. However, tumor recurrence is prevalent, highlighting the unmet medical need to develop therapeutic strategies to enhance the efficacy of RT in glioma. Focusing on the radiosensitizing potential of the currently approved drugs known to cross the blood-brain barrier can facilitate rapid clinical translation. Here, we assessed the role of catechol-O-methyltransferase (COMT), a key enzyme to degrade catecholamines and a drug target for Parkinson's disease, in glioma treatment. Analysis of The Cancer Genome Atlas data showed significantly higher COMT expression levels in both low-grade glioma and glioblastoma compared to normal brain tissues. Inhibition of COMT by genetic knockout or FDA-approved COMT inhibitors significantly sensitized glioma cells to RT in vitro and in vivo. Mechanistically, COMT inhibition in glioma cells led to mitochondria dysfunction and increased mitochondrial RNA release into the cytoplasm, activating the cellular antiviral double-stranded RNA sensing pathway and type I interferon (IFN) response. Elevated type I IFNs stimulated the phagocytic capacity of microglial cells, enhancing RT efficacy. Given the long-established safety record of the COMT inhibitors, these findings provide a solid rationale to evaluate them in combination with RT in patients with glioma. Significance: Inhibition of catechol-O-methyltransferase, a well-established drug target in Parkinson's disease, interferes with mitochondrial electron transport and induces mitochondrial double-stranded RNA leakage, activating type I interferon signaling and sensitizing glioma to radiotherapy.

Advancement of fluorescent aminopeptidase probes for rapid cancer detection-current uses and neurosurgical applications.

Surgical resection is considered for most brain tumors to obtain tissue diagnosis and to eradicate or debulk the tumor. Glioma, the most common primary malignant brain tumor, generally has a poor prognosis despite the multidisciplinary treatments with radical resection and chemoradiotherapy. Surgical resection of glioma is often complicated by the obscure border between the tumor and the adjacent brain tissues and by the tumor's infiltration into the eloquent brain. 5-aminolevulinic acid is frequently used for tumor visualization, as it exhibits high fluorescence in high-grade glioma. Here, we provide an overview of the fluorescent probes currently used for brain tumors, as well as those under development for other cancers, including HMRG-based probes, 2MeSiR-based probes, and other aminopeptidase probes. We describe our recently developed HMRG-based probes in brain tumors, such as PR-HMRG, combined with the existing diagnosis approach. These probes are remarkably effective for cancer cell recognition. Thus, they can be potentially integrated into surgical treatment for intraoperative detection of cancers.

Surgical resection of gliomas in the dominant inferior frontal gyrus: Consecutive case series and anatomy review of Broca’s area

IntroductionThere is a general lack of consensus on both anatomic definition and function of Broca’s area, often localized to the pars triangularis (pT) and pars opercularis (pOp) of the left inferior frontal gyrus (IFG). Given the belief that this region plays a critical role in expressive language functions, resective surgery is often avoided to preserve function. However, the putative role of Broca’s area in speech production has been recently challenged. The current study aims to investigate the plausibility of glioma resection and neurological outcomes in “Broca’s area”. MethodsWe report a single-surgeon, consecutive case series feasibility study describing the resection of gliomas within the IFG. Presentation, mapping, functional outcome, and extent of resection variables were considered for analysis. ResultsAll included patients had tumors located in the traditional “Broca’s area”, eight (53.33 %) additionally extending into the insular and subinsular regions. All patients except for one, presented with speech-language deficits preoperatively. Awake brain surgery for tumor resection with direct cortical and subcortical stimulation and intraoperative neuropsychological evaluation was carried out in all individuals. During stimulation, positive speech-language sites within the IFG were identified in ten patients. Two patients (13.33 %) experienced a decline in naming during intraoperative cognitive monitoring and thirteen (86.66 %) had a stable performance throughout surgery. At two-week follow-up, all patients had recovery of language functions compared to initial presentation. Overall extent of resection (EOR) was 60.35 % ( ± 29.60) with residual tumor being the greatest within the insular and subinsular areas. EOR was stratified in anatomical regions within the IFG, being the pOr the area with the greatest EOR (97.4 %), followed by the pT (84.1 %), pOp (83.8 %), and vPMC (80 %). ConclusionThe belief that Broca’s area is not safe to resect is challenged. Adequate mapping and careful patient selection allow maximum safe resection of tumors located in the traditional “Broca’s area”, with low risk of postoperative morbidity.

Effect of neoadjuvant iodine-125 brachytherapy upon resection of glioma

BackgroundA more extensive surgical resection of glioma contributes to improved overall survival (OS) and progression-free survival (PFS). However, some patients miss the chance of surgical resection when the tumor involves critical structures.PurposeThe present study aimed to assess the feasibility of neoadjuvant 125I brachytherapy followed by total gross resection for initially inoperable glioma.MethodsSix patients diagnosed with inoperable glioma due to invasion of eloquent areas, bihemispheric diffusion, or large tumor volume received 125I brachytherapy. Surgical resection was performed when the tumor shrank, allowing a safe resection, assessed by the neurosurgeons. Patients were followed up after surgery.ResultsShrinkage of the tumor after adjuvant 125I brachytherapy enabled a total gross resection of all six patients. Four patients were still alive at the last follow-up, with the longest survival time of more than 50 months, two of which returned to everyday life with a KPS of 100. Another two patients had neurological injuries with KPSs of 80 and 50, respectively. One patient with grade II glioma died 34 months, and another with grade IV glioma died 40 months after the combined therapy.ConclusionsIn the present study, the results demonstrated that 125I brachytherapy enabled a complete resection of patients with initially unresectable gliomas. 125I brachytherapy may offer a proper neoadjuvant therapy method for glioma.

Toxicity and Pharmacokinetic Profile for Single-Dose Injection of ABY-029: a Fluorescent Anti-EGFR Synthetic Affibody Molecule for Human Use.

ABY-029, a synthetic Affibody peptide, Z03115-Cys, labeled with a near-infrared fluorophore, IRDye® 800CW, targeting epidermal growth factor receptor (EGFR) has been produced under good manufacturing practices for a US Food and Drug Administration-approved first-in-use human study during surgical resection of glioma, as well as other tumors. Here, the pharmacology, phototoxicity, receptor activity, and biodistribution studies of ABY-029 were completed in rats, prior to the intended human use. Male and female Sprague Dawley rats were administered a single intravenous dose of varying concentrations (0, 245, 2449, and 24,490μg/kg corresponding to 10×, 100×, and 1000× an equivalent human microdose level) of ABY-029 and observed for up to 14days. Histopathological assessment of organs and tissues, clinical chemistry, and hematology were performed. In addition, pharmacokinetic clearance and biodistribution of ABY-029 were studied in subgroups of the animals. Phototoxicity and ABY-029 binding to human and rat EGFR were assessed in cell culture and on immobilized receptors, respectively. Histopathological assessment and hematological and clinical chemistry analysis demonstrated that single-dose ABY-029 produced no pathological evidence of toxicity at any dose level. No phototoxicity was observed in EGFR-positive and EGFR-negative glioma cell lines. Binding strength and pharmacokinetics of the anti-EGFR Affibody molecules were retained after labeling with the dye. Based on the successful safety profile of ABY-029, the 1000× human microdose 24.5mg/kg was identified as the no observed adverse effect level following intravenous administration. Conserved binding strength and no observed light toxicity also demonstrated ABY-029 safety for human use.

Local in vitro delivery of rapamycin from electrospun PEO/PDLLA nanofibers for glioblastoma treatment.

Rapamycin, a mammalian target of rapamycin inhibitor and anti-proliferative agent, is used to treat glioma and other malignancies, but its effectiveness is limited by the fact that it cannot be delivered in a targeted manner to the site of the tumor. To address this issue, we fabricated a mesh via electrospinning using two biodegradable materials, poly(lactic acid) (PLA) and polyethylene oxide (PEO) as a carrier for rapamycin delivery to the tumor. Nanofiber diameter decreased with increasing PLA concentration in the mixed solution. Scanning electron microscopy analysis revealed the smooth and uniform surface morphology of hybrid fibers. Fourier transform infrared spectroscopy analysis demonstrated that rapamycin was encapsulated in the polymer solution; encapsulation efficiency was high and stable over the range of drug concentrations from 0.5-2wt%. A correlation was observed between sustained release of the drug in vitro and cytotoxicity in cultured glioma cells. These results indicate that the PEO/poly(d,l-lactic acid) nanofiber mesh can be used as a targeted delivery system for rapamycin that can limit side effects and prevent locoregional recurrence following surgical resection of glioma.

Preliminary discussion of BCNU-loaded biodegradable implants for recurrent malignant gliomas

Objective To evaluate the safety and primary efficacy of BCNU-loaded biodegradable implants for the treatment of recurrent malignant gliomas. Methods From January 2011 to December 2012, 22 patients with recurrent malignant glioma treated at the Department of Neurosurgery, Sun Yat-sen University Cancer Center and the Department of Neurosurgeries of 5 hospitals in China were analyzed retrospectively. The BCNU-loaded implants were placed into the tumor cavities after surgical resection of gliomas. The adverse reactions of the patients within 28 d after procedure were documented in detail. Its safety was evaluated. The survival time and the efficacy of preliminary drug evaluation after placing the implants in patients were recorded. Results A total of 22 patients received local sustained release chemotherapy. The gliomas of 12 patients were totally resected, 8 were subtotally resected, and 2 were partially resected. Three BCNU-loaded biodegradable implants were implanted in 3 cases, 6 were implanted in 3 cases, 8 were implanted in 4 cases, 9 were implanted in 3 cases, 10 were implanted in 3 cases, and 12 were implanted in 6 cases. At day 28 after implantation, 11 patients did not have other treatment, 8 received the chemotherapeutic drugs based on nitrosoureas or temozolomide chemotherapy, and 3 received both radiotherapy and chemotherapy. The most common adverse reaction of the implants was subgaleal effusion (n=9). Other adverse reactions included rash (n=2), thrombocytopenia (n=1), and erythrocytopenia (n=1). The mean follow-up time was 55 months. Twenty of 22 patients died and 2 were still alive up to the last follow-up. The median survival time of the 22 patients was 322 d (95% CI 173-471 d). Conclusions The BCNU-loaded biodegradable implants are well tolerated and safe. The agents have a tendency of prolonging the survival time of patients with recurrent malignant glioma. It is worth conducting phase III clinical trial to evaluate the efficacy. Key words: Glioma; Neurosurgical procedures; Adjuvant chemotherapy

Resection extent of the supplementary motor area and post-operative neurological deficits in glioma surgery

Objective The supplementary motor area (SMA) is important for the prediction of post-operative symptoms after surgical resection of gliomas. We investigated the relationships between clinical factors and the resection range of SMA gliomas, and the post-operative neurological symptoms. Methods We retrospectively studied 18 consecutive surgeries for gliomas involving the SMA proper performed in 13 patients. Seven cases were recurrence of the tumour. Clinical factors and details of specific resection of the SMA proper (resection of posterior part, medial wall) and cingulate motor area (CMA) were examined. Results Eight cases suffered new post-operative neurological deficits. Six of these eight cases had transient deficits. Permanent deficits persisted in two cases with partial weakness or paresis, after rapid improvement of post-operative global weakness or hemiplegia, respectively. The risk of post-operative neurological deficits was not associated with the resection of the posterior part of the SMA proper or the CMA, but was associated with resection of the medial wall of the SMA proper. Surgery for recurrent tumour was associated with post-operative neurological deficits. The medial wall was frequently resected in recurrent cases. Discussion The frequency of post-operative neurological symptoms, including SMA syndrome, may be higher after resection of the medial wall of the SMA proper compared with the resection of only the lateral surface of the SMA proper.

Treatment of Glioma Using neuroArm Surgical System.

The use of robotic technology in the surgical treatment of brain tumour promises increased precision and accuracy in the performance of surgery. Robotic manipulators may allow superior access to narrow surgical corridors compared to freehand or conventional neurosurgery. This paper reports values and ranges of tool-tissue interaction forces during the performance of glioma surgery using an MR compatible, image-guided neurosurgical robot called neuroArm. The system, capable of microsurgery and stereotaxy, was used in the surgical resection of glioma in seven cases. neuroArm is equipped with force sensors at the end-effector allowing quantification of tool-tissue interaction forces and transmits force of dissection to the surgeon sited at a remote workstation that includes a haptic interface. Interaction forces between the tool tips and the brain tissue were measured for each procedure, and the peak forces were quantified. Results showed maximum and minimum peak force values of 2.89 N (anaplastic astrocytoma, WHO grade III) and 0.50 N (anaplastic oligodendroglioma, WHO grade III), respectively, with the mean of peak forces varying from case to case, depending on type of the glioma. Mean values of the peak forces varied in range of 1.27 N (anaplastic astrocytoma, WHO grade III) to 1.89 N (glioblastoma with oligodendroglial component, WHO grade IV). In some cases, ANOVA test failed to reject the null hypothesis of equality in means of the peak forces measured. However, we could not find a relationship between forces exerted to the pathological tissue and its size, type, or location.

P17.75 * UTILITY OF 3D SURGICAL PLANNING FOR RESECTION OF HIGH-GRADE GLIOMAS

OBJECTIVES: Surgical resection of gliomas involving eloquent brain areas carries a high risk of postoperative neurological deterioration. METHODS: Total of 129 patients (75 males, 54 females, mean age 45.5 years, range 20-70 years) underwent preoperative MRI with Gd-enhancement (3D-T1W, T2W, FLAIR, DTI-FT, fMRI). Brain tumors located in eloquent areas (Sawaya grade III) in 93 (72.1%) patients and close to eloquent areas (Sawaya grade II) in 36 (27.9%) patients. The surgical planning and tumor microsurgery resection were carried out using StealthStation navigation system (Medtronic Inc., USA). The surgical planning was performed with a 3D volumetric reconstruction of cerebral hemispheres' surface, tumor, corticospinal tracts, motor areas, ventricles, cerebral arteries, dural sinuses and cortical surface veins. The surgical trajectory and volume of safe tumor resection were defined and calculated preoperative. RESULTS: A gross total tumor resection was achieved in 54 (41.9%) patients, subtotal resection in 61 (47.3%), partial resection in 14 (10.8%). Glioblastomas (WHO Grade IV) were found in 61 (47.3%) cases, anaplastic gliomas (WHO Grade III) _ in 68 (52.7%). Median KPS score increased from 68.4 to 84.8 after surgery (p < 0.05). The neuronavigation system supports the ability of multimodal data sets integration and preoperative planning with using of 3D models presenting anatomical and functional structures. The 3D modeling reveals anatomical relations of tumor with the surrounding eloquent areas and vessels that creates conditions for determination of the optimal surgical tactics. The use of multimodal neuronavigation provided intraoperative orientation by comparing position of virtual structures from preoperative planning data with the anatomical structures in the operative field. CONCLUSION: The 3D surgical planning allows evaluating the risk of injury of eloquent structures, facilitates the orientation in operative field, and reduces the level of neurological disorders in operated patients.

Identifying malignant transformations in recurrent low grade gliomas using high resolution magic angle spinning spectroscopy

The objective of this study was to determine whether metabolic parameters derived from ex vivo analysis of tissue samples are predictive of biologic characteristics of recurrent low grade gliomas (LGGs). This was achieved by exploring the use of multivariate pattern recognition methods to generate statistical models of the metabolic characteristics of recurrent LGGs that correlate with aggressive biology and poor clinical outcome. Statistical models were constructed to distinguish between patients with recurrent gliomas that had undergone malignant transformation to a higher grade and those that remained grade 2. The pattern recognition methods explored in this paper include three filter-based feature selection methods (chi-square, gain ratio, and two-way conditional probability), a genetic search wrapper-based feature subset selection algorithm, and five classification algorithms (linear discriminant analysis, logistic regression, functional trees, support vector machines, and decision stump logit boost). The accuracy of each pattern recognition framework was evaluated using leave-one-out cross-validation and bootstrapping. The population studied included fifty-three patients with recurrent grade 2 gliomas. Among these patients, seven had tumors that transformed to grade 4, twenty-four had tumors that transformed to grade 3, and twenty-two had tumors that remained grade 2. Image-guided tissue samples were obtained from these patients using surgical navigation software. Part of each tissue sample was examined by a pathologist for histological features and for consistency with the tumor grade diagnosis. The other part of the tissue sample was analyzed with ex vivo nuclear magnetic resonance (NMR) spectroscopy. Distinguishing between recurrent low grade gliomas that transformed to a higher grade and those that remained grade 2 was achieved with 96% accuracy, using areas of the ex vivo NMR spectrum corresponding to myoinositol, 2-hydroxyglutarate, hypo-taurine, choline, glycerophosphocholine, phosphocholine, glutathione, and lipid. Logistic regression and decision stump boosting models were able to distinguish between recurrent gliomas that transformed to a higher grade and those that did not with 100% training accuracy (95% confidence interval [93-100%]), 96% leave-one-out cross-validation accuracy (95% confidence interval [87-100%]), and 96% bootstrapping accuracy (95% confidence interval [95-97%]). Linear discriminant analysis, functional trees, and support vector machines were able to achieve leave-one-out cross-validation accuracy above 90% and bootstrapping accuracy above 85%. The three feature ranking methods were comparable in performance. This study demonstrates the feasibility of using quantitative pattern recognition methods for the analysis of metabolic data from brain tissue obtained during the surgical resection of gliomas. All pattern recognition techniques provided good diagnostic accuracies, though logistic regression and decision stump boosting slightly outperform the other classifiers. These methods identified biomarkers that can be used to detect malignant transformations in individual low grade gliomas, and can lead to a timely change in treatment for each patient.

La chirurgie des gliomes cérébraux en 2008

Surgical resection of gliomas is a well-established treatment. It allows a histo-genetic diagnosis, a mass effect reduction, an intracranial hypertension treatment, a recovery of an eventual neurological deficit induced by the mass effect, but mostly brings a significant survival. New imaging sequences are optimizing the surgical management of brain tumors by bringing precisions on the tumor morphology, on cortical/subcortical eloquent areas (functional and diffusion MRI), on histology (spectroscopic MR). If the tumor is located in eloquent area, surgery is performed under electrostimulation control to take into account cerebral plasticity and to avoid postoperative functional deficits. Neuronavigation, per-operative echography, and per-operative MRI are recognized tools for optimizing the tumor resection. Ongoing researches concern the adjunction of local treatments within the surgical field (photodynamic therapy, chemotherapy, convection immunotherapy…), but also the development of minimal invasive procedures (radiosurgery, high intensity focalized ultrasounds, laser interstitial thermal therapy).

Combined Use of DES, EMG and MEP Monitoring, ECoG and EEG for Surgical Resection of Gliomas

Combined Use of DES, EMG and MEP Monitoring, ECoG and EEG for Surgical Resection of Gliomas

Diffusion-weighted MR imaging abnormalities in pediatric patients with surgically-treated intracranial mass lesions

Diffusion-weighted imaging (DWI) is a magnetic resonance imaging (MRI) technique that measures the degree of water diffusion in vivo. DWI abnormalities are frequently observed on immediate postoperative imaging following surgical resection of gliomas in adults. These abnormalities subsequently demonstrate contrast enhancement, which may be confused with lesion recurrence. The purpose of this study was to investigate the occurrence of these postoperative abnormalities in pediatric patients with intracranial mass lesions. Thirty-three consecutive patients <or=18 years old with a newly diagnosed intracranial mass lesion underwent MRI, including DWI, before and immediately after surgical treatment. The median patient age was 9.9 years (range 0.2-18 years). Supratentorial and infratentorial lesions were identified in 22 and 11 patients, respectively. Infiltrative and noninfiltrative, as well as benign and malignant lesions, were included. Postoperative imaging demonstrated areas of reduced diffusion adjacent to the resection cavity in 20 (61%) cases. The median volume of these areas was 1.7 cm3 (range 0.3 cm3-12.0 cm3). Subsequent imaging studies in 9 of the 18 cases showed contrast enhancement in the area corresponding to the DWI abnormality. There were no clinical deficits attributable to any of the diffusion abnormalities. There was no association between the occurrence of these abnormalities and whether the lesion was infiltrative, non-infiltrative, benign, or malignant. DWI abnormality on immediate postoperative MRI is common following surgery for newly diagnosed intracranial mass lesions in pediatric patients. Focal contrast enhancement in the postoperative period may be confused with recurrence for some lesions. Our study suggests that immediate postoperative DWI is useful in interpreting new areas of focal contrast enhancement on subsequent imaging in children who have had surgery for brain tumors.