J Neurosurg 117:1039–1052, 2012
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 (DVT2T1) to evaluate how the diffusive tumor-growing pattern affected the EOR achieved.
Results. The median preoperative tumor volume was 55 cm3, 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 DVT2T1 value (p < 0.0001). Progression-free survival is similarly influenced by histological subtype (fibrillary astrocytoma, p = 0.003), EOR (p < 0.0001), and DVT2T1 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 DVT2T1 value, the less extensive the currently possible resection, highlighting an apparent correlation between the DVT2T1 value itself and EOR (p < 0.0001).
Conclusions. The EOR and the DVT2T1 values are the strongest independent predictors in improving OS as well as in delaying tumor progression and malignant transformation. Furthermore, the DVT2T1 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.
Acta Neurochir (2012) 154:575–584.DOI 10.1007/s00701-011-1216-x
WHO grade II glioma (G2G) is a premalignant tumor, usually revealed by seizures in young patients living normal lives. G2G grows constantly and will inevitably become anaplastic. Surgical resection significantly increases the overall survival by delaying malignant transformation. Recently, a similar natural history was demonstrated in a patient with incidental G2G, with continuous growth and risk of anaplasia. Here, the aim was to study for the first time the functional results and extent of resection in a prospective series of patients who underwent resection for incidental G2G within eloquent areas.
Method G2G involving functional regions in the left dominant hemisphere was incidentally diagnosed in 11 asymptomatic patients. Resection was achieved in all cases after demonstration of a volumetric increase on serial MRIs. Intraoperative awake mapping was performed in the 11 patients.
Findings There were no cases of mortality or permanent postoperative deficit. A subtotal, total or even “supratotal” resection was achieved in the 11 cases, with no partial resections. All patients resumed normal social and professional lives, with no seizures (KPS 100). Due to slow tumor re-growth in three patients with subtotal resection, adjuvant chemotherapy was administrated in two cases and radiotherapy in one. With a mean follow-up of 40 months since surgery, there was no anaplastic transformation.
Conclusion These results show that surgery can be considered in incidental G2G, even in critical areas, with a minimal risk and optimal resection, thanks to intraoperative mapping. Such findings raise the question of an early detection.
J Neurosurg 116:365–372, 2012. DOI: 10.3171/2011.9.JNS111068
Low-grade gliomas (LGGs) are rarely diagnosed as an incidental, asymptomatic finding, and it is not known how the early surgical management of these tumors might affect outcome. The purpose of this study was to compare the outcomes of patients with incidental and symptomatic LGGs and determine any prognostic factors associated with those outcomes.
Methods. All patients treated by the lead author for an LGG incidentally discovered between 1999 and 2010 were retrospectively reviewed. “Incidental” was defined as a finding on imaging that was obtained for a reason not attributable to the glioma, such as trauma or headache. Primary outcomes included overall survival, progression-free survival (PFS), and malignant PFS. Patients with incidental LGGs were compared with a previously reported cohort of patients with symptomatic gliomas.
Results. Thirty-five patients with incidental LGGs were identified. The most common reasons for head imaging were headache not associated with mass effect (31.4%) and trauma (20%). Patients with incidental lesions had significantly lower preoperative tumor volumes than those with symptomatic lesions (20.2 vs 53.9 cm3, p < 0.001), were less likely to have tumors in eloquent locations (14.3% vs 61.9%, p < 0.001), and had a higher prevalence of females (57.1% vs 36%, p = 0.02). In addition, patients with incidental lesions were also more likely to undergo gross-total resection (60% vs 31.5%, p = 0.001) and had improved overall survival on Kaplan-Meier analysis (p = 0.039, Mantel-Cox test). Progression and malignant progression rates did not differ between the 2 groups. Univariate analysis identified pre- and postoperative volumes as well as the use of motor or language mapping as significant prognostic factors for PFS.
Conclusions. In this retrospective cohort of surgically managed LGGs, incidentally discovered lesions were associated with improved patient survival as compared with symptomatic LGGs, with acceptable surgical risks.
J Neurosurg 115:740–748, 2011. DOI: 10.3171/2011.6.JNS11252
Greater extent of resection (EOR) for patients with low-grade glioma (LGG) corresponds with improved clinical outcome, yet remains a central challenge to the neurosurgical oncologist. Although 5-aminolevulinic acid (5- ALA)–induced tumor fluorescence is a strategy that can improve EOR in gliomas, only glioblastomas routinely fluoresce following 5-ALA administration. Intraoperative confocal microscopy adapts conventional confocal technology to a handheld probe that provides real-time fluorescent imaging at up to 1000× magnification. The authors report a combined approach in which intraoperative confocal microscopy is used to visualize 5-ALA tumor fluorescence in LGGs during the course of microsurgical resection.
Methods. Following 5-ALA administration, patients with newly diagnosed LGG underwent microsurgical resection. Intraoperative confocal microscopy was conducted at the following points: 1) initial encounter with the tumor; 2) the midpoint of tumor resection; and 3) the presumed brain-tumor interface. Histopathological analysis of these sites correlated tumor infiltration with intraoperative cellular tumor fluorescence.
Results. Ten consecutive patients with WHO Grades I and II gliomas underwent microsurgical resection with 5-ALA and intraoperative confocal microscopy. Macroscopic tumor fluorescence was not evident in any patient. However, in each case, intraoperative confocal microscopy identified tumor fluorescence at a cellular level, a finding that corresponded to tumor infiltration on matched histological analyses.
Conclusions. Intraoperative confocal microscopy can visualize cellular 5-ALA–induced tumor fluorescence within LGGs and at the brain-tumor interface. To assess the clinical value of 5-ALA for high-grade gliomas in conjunction with neuronavigation, and for LGGs in combination with intraoperative confocal microscopy and neuronavigation, a Phase IIIa randomized placebo-controlled trial (BALANCE) is underway at the authors’ institution.
Acta Neurochir (2011) 153:1907–1917. DOI 10.1007/s00701-011-1125-z
Diffuse WHO grade II glioma (GIIG) involving the occipital lobe is a rare entity. Its surgical resection remains controversial as it implies inducing a permanent visual deficit. For the first time to our knowledge, we report a consecutive surgical series of patients who underwent an occipital lobectomy for an LGG invading visual structures.
Method Six right-handed patients harboring a GIIG revealed by seizures (normal examination except a quadrantanopsia in one case) and located within the occipital lobe (4 left and 2 right tumors) were submitted to surgery. Before making this decision, the benefit-to-risk ratio of the resection was extensively discussed with the patient and his/her family, especially concerning the price to pay to remove the tumor, that is, to voluntarily generate a permanent hemianopsia. All the procedures were performed under awake condition using intraoperative electrostimulation, in order to pursue the resection until sensory-motor and/or language structures were encountered.
Findings An extensive occipital lobectomy was achieved in the six patients, with identification and preservation of sensory-motor pathways in the two cases with a right tumor and detection of language pathways in the four cases with a left tumor. The mean extent of resection was 93% (range: 91–100%). All patients experienced an expected postoperative deficit of the visual field (homonymous hemianopsia). Nonetheless, the six patients resumed a normal social and professional life (KPS at 90 in the 6 cases) with a mean follow-up of 58 months (range: 3–147 months)—with adjuvant treatment in three cases (in addition to a reoperation in two of them).
Conclusions Our findings suggest that, despite a definitive hemianopsia, an extensive surgical resection can be considered in the rare cases of occipital GIIG involving the primary visual structures, with patients able to maintain a normal life—except regarding the medico-legal problem of driving.
Neurosurgery 66:1074-1084, 2010 DOI: 10.1227/01.NEU.0000369514.74284.78
Awake craniotomy with intraoperative electrical mapping is a reliable method to minimize the risk of permanent deficit during surgery for low-grade glioma located within eloquent areas classically considered inoperable. However, it could be argued that preservation of functional sites might lead to a lesser degree of tumor removal. To the best of our knowledge, the extent of resection has never been directly compared between traditional and awake procedures.
OBJECTIVE: We report for the first time a series of patients who underwent 2 consecutive surgeries without and with awake mapping.
METHODS: Nine patients underwent surgery for a low-grade glioma in functional sites under general anesthesia in other institutions. The resection was subtotal in 3 cases and partial in 6 cases. There was a postoperative worsening in 3 cases. We performed a second surgery in the awake condition with intraoperative electrostimulation. The resection was performed according to functional boundaries at both the cortical and subcortical levels.
RESULTS: Postoperative magnetic resonance imaging showed that the resection was complete in 5 cases and subtotal in 4 cases (no partial removal) and that it was improved in all cases compared with the first surgery (P = .04). There was no permanent neurological worsening. Three patients improved compared with the presurgical status. All patients returned to normal professional and social lives.
CONCLUSION: Our results demonstrate that awake surgery, known to preserve the quality of life in patients with low-grade glioma, is also able to significantly improve the extent of resection for lesions located in functional regions.
J Neurooncol (2010) 97:33–40. DOI 10.1007/s11060-009-0004-4
Recent evidence suggests the Akt-mTOR pathway may play a role in development of low-grade gliomas (LGG). We sought to evaluate whether activation of this pathway correlates with survival in LGG by examining expression patterns of proteins within this pathway.
Forty-five LGG tumor specimens from newly diagnosed patients were analyzed for methylation of the putative 50-promoter region of PTEN using methylationspecific PCR as well as phosphorylation of S6 and PRAS40 and expression of PTEN protein using immunohistochemistry. Relationships between molecular markers and overall survival (OS) were assessed using Kaplan-Meier methods and exact log-rank test. Correlation between molecular markers was determined using the Mann-Whitney U and Spearman Rank Correlation tests.
Eight of the 26 patients with methylated PTEN died, as compared to 1 of 19 without methylation. There was a trend towards statistical significance, with PTEN methylated patients having decreased survival (P = 0.128). Eight of 29 patients that expressed phospho-S6 died, whereas all 9 patients lacking p-S6 expression were alive at last follow-up. There was an inverse relationship between expression of phospho-S6 and survival (P = 0.029). There was a trend towards decreased survival in patients expressing phospho-PRAS40 (P = 0.077).
Analyses of relationships between molecular markers demonstrated a statistically significant positive correlation between expression of p-S6(235) and p-PRAS40 (P = 0.04); expression of p-S6(240) correlated positively with PTEN methylation (P = 0.04) and negatively with PTEN expression (P = 0.03). Survival of LGG patients correlates with phosphorylation of S6 protein. This relationship supports the use of selective mTOR inhibitors in the treatment of low grade glioma
Neurosurg Focus 28 (2):E8, 2010. DOI: 10.3171/2009.12.FOCUS09236
Recent surgical studies have demonstrated that the extent of resection is significantly correlated with median survival in WHO Grade II gliomas. Consequently, thanks to advances in intraoperative functional mapping, the authors questioned whether it is actually necessary to leave a “security” margin around eloquent structures.
Methods. The authors first reviewed the classic literature, especially that based on epilepsy surgery and functional neuroimaging techniques, which led them to propose the rule of a security margin. Second, they detailed new developments in the field of intrasurgical electrical mapping, especially with regard to subcortical stimulation of the projection and long-distance association pathways. On the basis of these advances, the removal of gliomas according to functional boundaries has recently been suggested, with no margin around eloquent structures.
Results. Comparative results showed that the rate of permanent deficit was similar with or without a security margin, that is, < 2%. However, a higher rate of transient neurological worsening in the immediate postsurgical period was associated with the absence of a margin, with recovery following adapted rehabilitation. On the other hand, the extent of resection was in essence improved with no margin.
Conclusions. This no-margin technique, based on the subpial dissection, and the repetition of both cortical and subcortical stimulation to preserve eloquent cortex as well as the white matter tracts (U-fibers, projection pathways, and long-distance connectivity) allow optimization of the extent of resection while preserving the quality of life (despite transitory impairment) thanks to mechanisms of brain plasticity.
Acta Neurochir (2009) 151:1359–1365. DOI 10.1007/s00701-009-0435-x
The appropriate management of low-grade gliomas is still a matter of debate. So far, there are no randomized studies that analyze the impact of surgical
resection on patient outcome. The value of the data obtained from the few retrospective reports available is often limited.
Patients and methods In the present study, we performed an analysis on data of 130 adult low-grade glioma patients. Extent of the resection was evaluated in correlation to the overall survival (OS) and progression-free survival (PFS) using Cox regression multivariate analysis.
Results Extended surgery was shown to prolong OS and PFS significantly. Re-surgery in the case of a tumor relapse has a significant impact on OS and PFS, too.
Conclusions In summary, we could retrospectively evaluate a large case series of well-defined low-grade gliomas patients with a long follow-up period showing that
extended surgery would be the most effective therapy for low-grade glioma patients even in recurrent diseases
Neurosurg Focus 27 (4):E4, 2009. (DOI: 10.3171/2009.8.FOCUS09137)
Low-grade gliomas ([LGGs] WHO Grade II) are slow-growing intrinsic cerebral lesions that diffusely infiltrate the brain parenchyma along white matter tracts and almost invariably show a progression toward malignancy. The treatment of these tumors forces the neurosurgeon to face uncommon difficulties and is still a subject of debate. At the authors’ institution, resection is the first option in the treatment of LGGs. It requires the combined efforts of a multidisciplinary team of neurosurgeons, neuroradiologists, neuropsychologists, and neurophysiologists, who together contribute to the definition of the location, extension, and extent of functional involvement that a specific lesion has caused in a particular patient. In fact, each tumor induces specific modifications of the brain functional network, with high interindividual variability. This requires that each treatment plan is tailored to the characteristics of the tumor and of the patient. Consequently, surgery is performed according to functional and anatomical boundaries to achieve the maximal resection with maximal functional preservation. The identification of eloquent cerebral areas, which are involved in motor, language, memory, and visuospatial functions and have to be preserved during surgery, is performed through the intraoperative use of brain mapping techniques. The use of these techniques extends surgical indications and improves the extent of resection, while minimizing the postoperative morbidity and safeguarding the patient’s quality of life.
In this paper the authors present their paradigm for the surgical treatment of LGGs, focusing on the intraoperative neurophysiological monitoring protocol as well as on the brain mapping technique. They briefly discuss the results that have been obtained at their institution since 2005 as well as the main critical points they have encountered when using this approach.
Neurosurg Focus 27 (2):E7, 2009
Despite the report of recent experiences of insular surgery in the past decade, there has been no series specifically dedicated to studying functional outcome following resection of insular WHO Grade II gliomas involving the dominant hemisphere, in patients with no or only mild preoperative language deficit. In this article, the authors analyze the contribution of awake mapping for preservation of brain function, especially language, in a homogeneous series of 24 patients who underwent surgery for insular Grade II gliomas within the dominant insular lobe.
Twenty-four patients underwent surgery for an insular Grade II glioma involving the dominant hemisphere (22 left, 2 right), revealed by seizures in all but 1 case. The preoperative neurological examination result was normal in 17 patients (71%), whereas 7 patients presented with language disorders detected using an accurate language assessment performed by a speech therapist. All surgeries were performed on awake patients utilizing intra-operative language mapping involving cortical and subcortical stimulation.
There were no intrasurgical complications or postsurgical sensorimotor deficits. Despite an immediate postoperative language worsening in 12 cases (50%), all patients recovered to a normal status within 3 months, and 6 cases even improved in comparison with their preoperative examination results. The 24 patients returned to normal social and professional lives. Moreover, the surgery had a favorable impact on epilepsy in all but 4 cases (83%). On control MR imaging, 62.5% of resections were total or subtotal. Three patients underwent a second or third awake surgery, with no additional deficit. All but 2 patients (92%) are alive after a mean follow-up of 3 years (range 3–133 months).
Although insular surgery was long believed to be too risky, the present results show that the rate of permanent deficit, especially dysphasia, following resection of Grade II gliomas involving the dominant insula has been dramatically reduced (none in this patient series), thanks to the systematic use of intraoperative awake mapping, even in cases of repeated operations. Furthermore, patient quality of life may be improved due to a decrease of epilepsy after surgery. Thus, the authors suggest systematically considering resection when an insular Grade II glioma is diagnosed after seizures in a patient with no or mild deficit, even a glioma invading the dominant hemisphere.