Edouard Dezamis

Epileptic seizures in diffuse low-grade gliomas in adults

Diffuse low-grade gliomas are highly epileptogenic brain tumours. We aimed to explore the natural course of epileptic seizures, their predictors and the prognostic significance of their occurrence in adult patients harbouring a diffuse low-grade glioma. An observational retrospective multicentre study examined 1509 patients with diffuse low-grade gliomas to identify mutual interactions between tumour characteristics, tumour course and epileptic seizures. At diagnosis, 89.9% of patients had epileptic seizures. Male gender (P = 0.003) and tumour location within functional areas (P = 0.001) were independent predictors of a history of epileptic seizures at diagnosis. Tumour volume, growth velocity, cortical location, histopathological subtype or molecular markers did not significantly affect epileptic seizure occurrence probability. Prolonged history of epileptic seizures (P < 0.001), insular location (P = 0.003) and tumour location close to functional areas (P = 0.038) were independent predictors of uncontrolled epileptic seizures at diagnosis. Occurrence of epileptic seizures (P < 0.001), parietal (P = 0.029) and insular (P = 0.002) locations were independent predictors of uncontrolled epileptic seizures after oncological treatment. Patient age (P < 0.001), subtotal (P = 0.007) and total (P < 0.001) resections were independent predictors of total epileptic seizure control after oncological treatment. History of epileptic seizures at diagnosis and total surgical resection were independently associated with increased malignant progression-free (P < 0.001 and P < 0.001) and overall (P < 0.001 and P = 0.016) survivals. Epileptic seizures are independently associated with diffuse low-grade glioma prognosis. Patients diagnosed with epileptic seizures and those with complete and early surgical resections have better oncological outcomes. Early and maximal surgical resection is thus required for diffuse low-grade gliomas, both for oncological and epileptological purposes.

Diffuse low-grade oligodendrogliomas extend beyond MRI-defined abnormalities

Background: Imaging determinations of the spatial extent of diffuse low-grade gliomas (DLGGs) are of paramount importance in evaluating the risk-to-benefit ratio of surgical resection. However, it is not clear how accurately preoperative conventional MRI can delineate DLGGs. Methods: We report a retrospective histologic and imaging correlation study in 16 adult patients who underwent serial stereotactic biopsies for the diagnosis of untreated supratentorial well-defined and non–contrast-enhanced DLGG, in whom biopsy samples were taken within and beyond (OutBSs) MRI-defined abnormalities. Results: Thirty-seven OutBSs that extended from 10 to 26 mm beyond MRI-defined abnormalities were studied. Immunostaining revealed MIB-1–positive cells (i.e., cycling cells) in all but 2 of the OutBSs. None of the MIB-1–positive cells coexpressed glial fibrillary acidic protein, and all of them coexpressed OLIG2. MIB-1–positive cells were cycling isolated tumor cells, because 1) their morphologic characteristics reflected those of tumor cells, 2) the number of MIB-1–positive cells per square centimeter was significantly higher than that of controls, 3) the number of MIB-1–positive cells per square centimeter was positively correlated with the tumor growth fraction (p = 0.012), and 4) the number of MIB-1–positive cells per square centimeter in OutBSs decreased with distance from the tumor (p = 0.003). Conclusions: This study demonstrates, using a multiscale correlative approach, that conventional MRI underestimates the actual spatial extent of diffuse low-grade gliomas (DLGGs), even when they are well delineated. These results suggest that an extended resection of a margin beyond MRI-defined abnormalities, whenever feasible in noneloquent brain areas, might improve the outcome of DLGGs.

Three-tesla functional MR language mapping: Comparison with direct cortical stimulation in gliomas

Objective: To evaluate the accuracy of functional MRI (fMRI) at 3T, as currently used in the preoperative mapping of language areas, compared with direct cortical stimulation (DCS) during awake surgery, in patients with supratentorial gliomas; and to identify clinical, histopathologic, and radiologic factors associated with fMRI/DCS discrepancies. Methods: Language mapping with fMRI and DCS of 40 consecutive patients with gliomas (24 low-grade, 16 high-grade) in functional areas were retrospectively analyzed. Three block-designed tasks were performed during fMRI (letter word generation, category word generation, semantic association). During awake surgery, eloquent areas were mapped using DCS, blinded to fMRI. A site-by-site comparison of the 2 techniques was performed using a cortical grid. fMRI sensitivity and specificity were calculated using DCS as the reference. Associations of clinical, histopathologic, and radiologic features (including relative cerebral blood volume [rCBV] measured with dynamic susceptibility contrast MRI) with fMRI false-positive and false-negative occurrence were assessed using hierarchical logistic regressions. Results: Of 2,114 stimulated cortical sites, 103 were positive for language during DCS. Sensitivity and specificity of language fMRI combining the 3 tasks reached 37.1% (95% confidence interval [CI] 20.7–57.2) and 83.4% (95% CI 77.1–88.3), respectively. Astrocytoma subtype (odds ratio [OR] 2.50 [1.32–4.76]; p = 0.007), tumor rCBV <1.5 (OR 2.17 [1.08–4.35]; p = 0.03), higher cortical rCBV (OR 2.22 [1.15–4.17]; p = 0.02), and distance to tumor >1 cm (OR 2.46 [1.82–3.32]; p ≤ 0.001) were independently associated with fMRI false-positive occurrence. Conclusions: There are pitfalls in preoperative fMRI as currently used in preoperative language mapping in glioma patients, made more complicated when high-grade and hyperperfused tumors are evaluated.

Dynamic imaging response following radiation therapy predicts long-term outcomes for diffuse low-grade gliomas.

Quantitative imaging assessment of radiation therapy (RT) for diffuse low-grade gliomas (DLGG) by measuring the velocity of diametric expansion (VDE) over time has never been studied. We assessed the VDE changes following RT and determined whether this parameter can serve as a prognostic factor. We reviewed a consecutive series of 33 adults with supratentorial DLGG treated with first-line RT with available imaging follow-up (median follow-up, 103 months). Before RT, all patients presented with a spontaneous tumor volume increase (positive VDE, mean 5.9 mm/year). After RT, all patients demonstrated a tumor volume decrease (negative VDE, mean, -16.7 mm/year) during a mean 49-month duration. In univariate analysis, initial tumor volume (>100 cm(3)), lack of IDH1 expression, p53 expression, high proliferation index, and fast post-RT tumor volume decrease (VDE at -10 mm/year or faster, fast responders) were associated with a significantly shorter overall survival (OS). The median OS was significantly longer (120.8 months) for slow responders (post-RT VDE slower than -10.0 mm/year) than for fast responders (47.9 months). In multivariate analysis, fast responders, larger initial tumor volume, lack of IDH1 expression, and p53 expression were independent poor prognostic factors for OS. A high proliferation index was significantly more frequent in the fast responder subgroup than in the slow responder subgroup. We conclude that the pattern of post-RT VDE changes is an independent prognostic factor for DLGG and offers a quantitative parameter to predict long-term outcomes. We propose to monitor individually the post-RT VDE changes using MRI follow-up, with particular attention to fast responders.

Imaging growth and isocitrate dehydrogenase 1 mutation are independent predictors for diffuse low-grade gliomas

BACKGROUND We explored whether spontaneous imaging tumor growth (estimated by the velocity of diametric expansion) and isocitrate dehydrogenase 1 (IDH1) mutation (estimated by IDH1 immunoexpression) were independent predictors of long-term outcomes of diffuse low-grade gliomas in adults. METHODS One hundred thirty-one adult patients with newly diagnosed supratentorial diffuse low-grade gliomas were retrospectively studied. RESULTS Isocitrate dehydrogenase 1 mutations were present in 107 patients. The mean spontaneous velocity of diametric expansion was 5.40 ± 5.46 mm/y. During follow-up (mean, 70 ± 54.7 mo), 56 patients presented a malignant transformation and 23 died. The median malignant progression-free survival and the overall survival were significantly longer in cases of slow velocity of diametric expansion (149 and 198 mo, respectively) than in cases of fast velocity of diametric expansion (46 and 82 mo; P < .001 and P < .001, respectively) and in cases with IDH1 mutation (100 and 198 mo, respectively) than in cases without IDH1 mutation (72 mo and not reached; P = .028 and P = .001, respectively). In multivariate analyses, spontaneous velocity of diametric expansion and IDH1 mutation were independent prognostic factors for malignant progression-free survival (P < .001; hazard ratio, 4.23; 95% CI, 1.81-9.40 and P = .019; hazard ratio, 2.39; 95% CI, 1.19-4.66, respectively) and for overall survival (P < .001; hazard ratio, 26.3; 95% CI, 5.42-185.2 and P = .007; hazard ratio, 17.89; 95% CI, 2.15-200.1, respectively). CONCLUSIONS The spontaneous velocity of diametric expansion and IDH1 mutation status are 2 independent prognostic values that should be obtained at the beginning of the management of diffuse low-grade gliomas in adults.

Long-term results of carmustine wafer implantation for newly diagnosed glioblastomas: a controlled propensity-matched analysis of a French multicenter cohort

BACKGROUND The standard of care for newly diagnosed glioblastoma is maximal safe surgical resection, followed by chemoradiation therapy. We assessed carmustine wafer implantation efficacy and safety when used in combination with standard care. METHODS Included were adult patients with (n = 354, implantation group) and without (n = 433, standard group) carmustine wafer implantation during first surgical resection followed by chemoradiation standard protocol. Multivariate and case-matched analyses (controlled propensity-matched cohort, 262 pairs of patients) were conducted. RESULTS The median progression-free survival was 12.0 months (95% CI: 10.7-12.6) in the implantation group and 10.0 months (9.0-10.0) in the standard group and the median overall survival was 20.4 months (19.0-22.7) and 18.0 months (17.0-19.0), respectively. Carmustine wafer implantation was independently associated with longer progression-free survival in patients with subtotal/total surgical resection in the whole series (adjusted hazard ratio [HR], 0.76 [95% CI: 0.63-0.92], P = .005) and after propensity matching (HR, 0.74 [95% CI: 0.60-0.92], P = .008), whereas no significant difference was found for overall survival (HR, 0.95 [0.80-1.13], P = .574; HR, 1.06 [0.87-1.29], P = .561, respectively). Surgical resection at progression whether alone or combined with carmustine wafer implantation was independently associated with longer overall survival in the whole series (HR, 0.58 [0.44-0.76], P < .0001; HR, 0.54 [0.41-0.70], P < .0001, respectively) and after propensity matching (HR, 0.56 [95% CI: 0.40-0.78], P < .0001; HR, 0.46 [95% CI: 0.33-0.64], P < .0001, respectively). The higher postoperative infection rate in the implantation group did not affect survival. CONCLUSIONS Carmustine wafer implantation during surgical resection followed by the standard chemoradiation protocol for newly diagnosed glioblastoma in adults resulted in a significant progression-free survival benefit.

Clinical, Imaging, Histopathological and Molecular Characterization of Anaplastic Ganglioglioma

Anaplastic ganglioglioma (AGG) is a rare and malignant variant of ganglioglioma. According to the World Health Organization classification version 2016, their histopathological grading criteria are still ill-defined. The aim of the present study was to assess the clinical, imaging, histopathological, and molecular characteristics and outcomes of AGGs in a large consecutive and retrospective adult and pediatric case series. Eighteen patients with AGGs (13 adults and 5 children) were identified (14 de novo and 4 secondary) from a cohort of 222 gangliogliomas (GG) (8%) treated at our institution between 2000 and 2015. AGGs represented a very aggressive disease with poor outcome (median progression-free survival, 10 months; median overall survival, 27 months). They were located in the temporal lobe only in 22% and presented with seizures (44%) or increased intracranial pressure (44%) at diagnosis. Concerning histopathological and molecular data, they shared morphological characteristics and BRAF V600E mutation (39%) with their benign counterparts but also showed hTERT promoter mutation (61%), p53 accumulation (39%), ATRX loss (17%), or p.K27M H3F3A mutation (17%). AGGs are malignant neoplasms requiring aggressive oncological treatment. In the perspective of targeted therapies, AGGs should be screened for BRAF V600E, hTERT, ATRX, and mutations of histone genes.

Postoperative Recovery of Hippocampal Contralateral Diffusivity in Medial Temporal Lobe Epilepsy

Summary:  Purpose: To search for a recovery after surgery of mean diffusivity (MD) values in the contralateral nonsclerotic hippocampus of patients with medial temporal lobe epilepsy (MTLE) and hippocampal sclerosis (HS).

Combining intraoperative carmustine wafers and Stupp regimen in multimodal first-line treatment of primary glioblastomas

Abstract Background. The study investigated if intraoperative use of carmustine wafers, particularly in combination with Stupp regimen, is a viable and safe first-line treatment option of glioblastomas. Methods. Eighty-three consecutive adult patients (50 men; mean age 60 years) with newly diagnosed supratentorial primary glioblastomas that underwent surgical resection with intraoperative carmustine wafers implantation (n = 7.1 ± 1.7) were retrospectively studied. Results. The median overall survival (OS) was 15.8 months with 56 patients dying over the course of the study. There was no significant association between the number of implanted carmustine wafers and complication rates (four surgical site infections, one death). The OS was significantly longer in Stupp regimen patients (19.5 months) as compared with patients with other postoperative treatments (13 months; p = 0.002). In addition patients with eight or more implanted carmustine wafers survived longer (24.5 months) than patients with seven or less implanted wafers (13 months; p = 0.021). Finally, regardless of the number of carmustine wafers, median OS was significantly longer in patients with a subtotal or total resection (21.5 months) than in patients with a partial resection (13 months; p = 0.011). Conclusions. The intraoperative use of carmustine wafers in combination with Stupp regimen is a viable first-line treatment option of glioblastomas. The prognostic value of this treatment association should be evaluated in a multicenter trial, ideally in a randomized and placebo-controlled one.

Delaying standard combined chemoradiotherapy after surgical resection does not impact survival in newly diagnosed glioblastoma patients.

BACKGROUND To assess the influence of the time interval between surgical resection and standard combined chemoradiotherapy on survival in newly diagnosed and homogeneously treated (surgical resection plus standard combined chemoradiotherapy) glioblastoma patients; while controlling confounding factors (extent of resection, carmustine wafer implantation, functional status, neurological deficit, and postoperative complications). METHODS From 2005 to 2011, 692 adult patients (434 men; mean of 57.5 ± 10.8 years) with a newly diagnosed glioblastoma were enrolled in this retrospective multicentric study. All patients were treated by surgical resection (65.5% total/subtotal resection, 34.5% partial resection; 36.7% carmustine wafer implantation) followed by standard combined chemoradiotherapy (radiotherapy at a median dose of 60 Gy, with daily concomitant and adjuvant temozolomide). Time interval to standard combined chemoradiotherapy was analyzed as a continuous variable and as a dichotomized variable using median and quartiles thresholds. Multivariate analyses using Cox modeling were conducted. RESULTS The median progression-free survival was 10.3 months (95% CI, 10.0-11.0). The median overall survival was 19.7 months (95% CI, 18.5-21.0). The median time to initiation of combined chemoradiotherapy was 1.5 months (25% quartile, 1.0; 75% quartile, 2.2; range, 0.1-9.0). On univariate and multivariate analyses, OS and PFS were not significantly influenced by time intervals to adjuvant treatments. On multivariate analysis, female gender, total/subtotal resection and RTOG-RPA classes 3 and 4 were significant independent predictors of improved OS. CONCLUSIONS Delaying standard combined chemoradiotherapy following surgical resection of newly diagnosed glioblastoma in adult patients does not impact survival.