Alexandre Roux

Recurrent glioblastomas in the elderly after maximal first-line treatment: does preserved overall condition warrant a maximal second-line treatment?

A growing literature supports maximal safe resection followed by standard combined chemoradiotherapy (i.e. maximal first-line therapy) for selected elderly glioblastoma patients. To assess the prognostic factors from recurrence in elderly glioblastoma patients treated by maximal safe resection followed by standard combined chemoradiotherapy as first-line therapy. Multicentric retrospective analysis comparing the prognosis and optimal oncological management of recurrent glioblastomas between 660 adult patients aged of < 70 years (standard group) and 117 patients aged of ≥70 years (elderly group) harboring a supratentorial glioblastoma treated by maximal first-line therapy. From recurrence, both groups did not significantly differ regarding Karnofsky performance status (KPS) (p = 0.482). Oncological treatments from recurrence significantly differed: patients of the elderly group received less frequently oncological treatment from recurrence (p < 0.001), including surgical resection (p < 0.001), Bevacizumab therapy (p < 0.001), and second line chemotherapy other than Temozolomide (p < 0.001). In multivariate analysis, Age ≥70 years was not an independent predictor of overall survival from recurrence (p = 0.602), RTOG-RPA classes 5–6 (p = 0.050) and KPS at recurrence <70 (p < 0.001), available in all cases, were independent significant predictors of shorter overall survival from recurrence. Initial removal of ≥ 90% of enhancing tumor (p = 0.004), initial completion of the standard combined chemoradiotherapy (p = 0.007), oncological treatment from recurrence (p < 0.001), and particularly surgical resection (p < 0.001), Temozolomide (p = 0.046), and Bevacizumab therapy (p = 0.041) were all significant independent predictors of longer overall survival from recurrence. Elderly patients had substandard care from recurrence whereas age did not impact overall survival from recurrence contrary to KPS at recurrence <70. Treatment options from recurrence should include repeat surgery, second line chemotherapy and anti-angiogenic agents.

Extent of resection and Carmustine wafer implantation safely improve survival in patients with a newly diagnosed glioblastoma: a single center experience of the current practice

For newly diagnosed glioblastomas treated with resection in association with the standard combined chemoradiotherapy, the impact of Carmustine wafer implantation remains debated regarding postoperative infections, quality of life, and feasibility of adjuvant oncological treatments. To assess together safety, tolerance and efficacy of Carmustine wafer implantation and of extent of resection for glioblastoma patients in real-life experience. Observational retrospective monocentric study including 340 consecutive adult patients with a newly diagnosed supratentorial glioblastoma who underwent surgical resection with (n = 123) or without (n = 217) Carmustine wafer implantation as first-line oncological treatment. Carmustine wafer implantation and extent of resection did not significantly increase postoperative complications, including postoperative infections (p = 0.269, and p = 0.446, respectively). Carmustine wafer implantation and extent of resection did not significantly increase adverse events during adjuvant oncological therapies (p = 0.968, and p = 0.571, respectively). Carmustine wafer implantation did not significantly alter the early postoperative Karnofsky performance status (p = 0.402) or the Karnofsky performance status after oncological treatment (p = 0.636) but a subtotal or total surgical resection significantly improved those scores (p < 0.001, and p < 0.001, respectively). Carmustine wafer implantation, subtotal and total resection, and standard combined chemoradiotherapy were independently associated with longer event-free survival (adjusted Hazard Ratio (aHR), 0.74 [95% CI 0.55–0.99], p = 0.043; aHR, 0.70 [95% CI 0.54–0.91], p = 0.009; aHR, 0.40 [95% CI 0.29–0.55], p < 0.001, respectively) and with longer overall survival (aHR, 0.69 [95% CI 0.49–0.96], p = 0.029; aHR, 0.52 [95% CI 0.38–0.70], p < 0.001; aHR, 0.58 [95% CI 0.42–0.81], p = 0.002, respectively). Carmustine wafer implantation in combination with maximal resection, followed by standard combined chemoradiotherapy is safe, efficient, and well-tolerated in newly diagnosed supratentorial glioblastomas in adults.

Left frontal meningioangiomatosis associated with type IIIc focal cortical dysplasia causing refractory epilepsy and literature review

BACKGROUND We report the surgical management of a lesional drug-resistant epilepsy caused by a meningioangiomatosis associated with a type IIIc focal cortical dysplasia located in the left supplementary motor area in a young male patient. CASE DESCRIPTION A first anatomically based partial surgical resection was performed on an 11-year-old under general anesthesia without intraoperative mapping, which allowed for postoperative seizure control (Engel IA) for 6 years. The patient then exhibited intractable right sensatory and aphasic focal onset seizures despite 2 appropriate antiepileptic drugs. A second functional-based surgical resection was performed using intraoperative corticosubcortical functional mapping with direct electrical stimulation under awake conditions. A complete surgical resection was performed, and a left partial supplementary motor area syndrome was observed. At 6 months postoperatively, the patient is seizure free (Engel IA) with an ongoing decrease in antiepileptic drug therapy. CONCLUSIONS Intraoperative functional brain mapping can be applied to preserve the brain function and networks around a meningioangiomatosis to facilitate the resection of potentially epileptogenic perilesional dysplastic cortex and to tailor the extent of resection to functional boundaries.

Do not omit the grade of malignancy when correlating the lobar location of diffuse gliomas and the risk of preoperative epileptic seizures

To the Editor, We enjoyed reading the recent paper by Zhang et al., published in Neurosurgical Review, entitled ‘Correlation between glioma location and preoperative seizures: a systematic review and meta-analysis’ [1]. The authors are to be congratulated for this effort, which confirms that glioma location—as defined on a lobar basis—has an impact on the risk of epileptic seizures at the time of diagnosis in patients with diffuse gliomas (grades II, III, and IV gliomas according to the World Health Organisation). The authors acknowledge that the risk of gliomarelated seizures varies relative to the World Health Organisation grade of malignancy (from 60 to 100% for grade II, 50–60% for grade III, and 25–50% for grade IV gliomas) [2]. However, we wonder why the authors did not stratify their analysis according to the WHO grade of malignancy? The grade of malignancy, which directly correlates with the risk of glioma-related seizures, is a confounder that should be incorporated in the present meta-analysis, which comprises grades II, III, and IV gliomas. Indeed, it is known that the WHO grade of malignancy varies with tumour location [3]: grade IV gliomas are reported more frequently in the parieto-temporo-occipital junction, which may account for the observed lower risk of preoperative seizure in occipital lobe gliomas (OR = 0.53, 95% CI = 0.32–0.88, p = 0.014), and grade II gliomas are reported more frequently in frontal and insular lobes, which may account for the observed higher risk of preoperative seizure in frontal lobe gliomas (OR = 1.51, 95% CI = 1.09–2.09, p = 0.013). This is a main limitation of this important study. As an illustration, one out the 16 studies incorporated in the present meta-analysis, which contributes to 34.9% of patients (1509/4323), included only grade II gliomas [2]. This may account for the reported high heterogeneity of the risk of preoperative seizure, as stated by the authors, and particularly for frontal lobe location. An explanation of the links between glioma location, glioma grade of malignancy, and risk of preoperative seizure may lie in the complexity of the glioma-related epileptogenic mechanisms, which are multifactorial and intermixed, and in the location of the epileptogenic foci, which are often close to the glioma core [4–6]. The glioma characteristics (including the grade of malignancy and the molecular status) may account for varying glioma-related epileptogenic factors and the glioma location may account for varying brain-related epileptogenic factors. As a consequence, the risk of preoperative seizure, resulting from the intermix between glioma and the brain, justify to study altogether the glioma grade of malignancy and the glioma location when assessing the risk of seizures in diffuse gliomas. To help the readers get a better idea of the contribution of the above discussed parameters, we strongly encourage the authors to add the glioma grade stratification to the present metaanalysis in order to refine and strengthen their conclusions. * Johan Pallud j.pallud@ch-sainte-anne.fr; johanpallud@hotmail.com

Letter to the editor: local alkylating chemotherapy applied immediately after 5-ALA guided resection of glioblastoma does not provide additional benefit

We enjoyed reading the recent paper by Sage et al. [1]. The authors are to be congratulated for this innovative experiment of 5-aminolevulinic acid (5-ALA) guided surgical resection combined with Carmustine wafer implantation (CWI) in an adult patient with newly-diagnosed glioblastoma. As suggested by the authors, this approach to treating glioblastomas appears quite promising and a randomized clinical trial is surely needed. However, we have concerns about how their findings have been presented as well as discussed in the context of the existing literature on the treatment of glioblastoma with CWI. We have also studied the impact of CWI in patients with glioblastomas in the Department of Neurosurgery of SainteAnne Hospital, University Paris Descartes [2] as well as in collaboration with the Neuro-oncology Club of the French Society of Neurosurgery [3, 4]. First, the authors failed to fully present the findings of the phase III study by Westphal et al. [5]. While Westphal et al. [5] stated in their subgroup of patients with grade IV glioblastoma that no significant benefit for CWI was found in univariate analysis, they found prolonged survival to be significant in this subgroup using a multivariate analysis (Cox proportional hazards model; p = 0.040; risk reduction for death of 31%; 95% CI 3–51). In our own experience [2, 4] we have also observed 2-months improvement in median survival with a significant benefit in overall survival and progression-free survival. Second, while the authors found no improvement in overall survival for CWI at first surgery, whether using a univariate/multivariate analysis of the whole series or a subgroup with a propensity score matching, they did not report the impact of CWI on progression-free survival. However, their study seems to suggest a possible positive impact of CWI on progression-free survival. In their Fig. 1a, Sage et al. show that the % of patients surviving with CWI (green line) is higher than those without CWI (blue line) during the first 2 years of follow-up. In accordance, the 12-month survival was significantly higher in the CWI group (54.4%) than in the control group (35.9%; p = 0.009). Thus, it would have been highly informative if the authors had presented progression-free survival to better understand the whole prognostic impact of these different surgical strategies. Our group has studied the impact of CWI on progressionfree survival in adult patients with newly-diagnosed glioblastomas (n = 787) treated by surgical resection followed by standard chemoradiation therapy. We found that CWI (n = 354) significantly improved progression-free survival (adjusted hazard ratio 0.76 [95% CI 0.63–0.92], p = 0.005 in the whole series; adjusted hazard ratio 0.74 [95% CI 0.60–0.92], p = 0.008 after propensity matching) but not overall survival (adjusted hazard ratio 0.95 [0.80–1.13], p = 0.574 in the whole series; adjusted hazard ratio 1.06 [0.87–1.29], p = 0.561 after propensity matching), both in whole series and in subgroup after propensity matching using a methodology similar to Pallud et al. [4]. Possible explanations for this finding include: the absence of true beneficial effect of CWI, the impact of subsequent salvage therapies administered during progression(s), including another surgical resection(s) or CWI(s) that could decrease the survival benefit of the first-line oncological treatment. Third, we found a number of methodological issues that could have impacted the study outcome and could help guide the design of future studies: (1) a quantitative analysis of the extent of resection should have been incorporated into * Johan Pallud j.pallud@ch-sainte-anne.fr; johanpallud@hotmail.com

Epileptic seizures in anaplastic gangliogliomas

Abstract Aim: Prevalence and predictors of epileptic seizures are unknown in the malignant variant of ganglioglioma. Methods: In a retrospective exploratory dataset of 18 supratentorial anaplastic World Health Organization grade III gangliogliomas, we studied: (i) the prevalence and predictors of epileptic seizures at diagnosis; (ii) the evolution of seizures during tumor evolution; (iii) seizure control rates and predictors of epilepsy control after oncological treatments. Results: Epileptic seizures prevalence progresses throughout the natural course of anaplastic gangliogliomas: 44% at imaging discovery, 67% at histopathological diagnosis, 69% following oncological treatment, 86% at tumor progression, and 100% at the end-of-life phase. The medical control of seizures and their refractory status worsened during the tumor’s natural course: 25% of uncontrolled seizures at histopathological diagnosis, 40% following oncological treatment, 45.5% at tumor progression, and 45.5% at the end-of-life phase. Predictors of seizures at diagnosis appeared related to the tumor location (i.e. temporal and/or cortical involvement). Prognostic parameters of seizure control after first-line oncological treatment were temporal tumor location, eosinophilic granular bodies, TP53 mutation, and extent of resection. Prognostic parameters of seizure control at tumor progression were a history of epileptic seizures at diagnosis, seizure control after first-line oncological treatment, eosinophilic granular bodies, and TP53 mutation. Conclusion: Epileptic seizures are frequently observed in anaplastic gangliogliomas and both prevalence and medically refractory status worsen during the tumor’s natural course. Both oncological and antiepileptic treatments should be employed to improve the control of epileptic seizures and the quality of life of patients harboring an anaplastic ganglioglioma.