Thierry Faillot

Intra-Operative Direct Electrical Stimulations of the Central Nervous System: The Salpetriere Experience With 60 Patients

Summary¶ Indications of surgical treatment for lesions in the central nervous system depend on the risk of a definitive neurological deficit, related to the benefit of resection. Detection of eloquent areas is then necessary because of major individual variability. Neuro-imaging functional techniques are in development and are beginning to be efficient for cortical sensorymotor mapping, but still lack sensitivity and specificity for language mapping, and remain unable to give real-time data during surgery and to perform sub-cortical mapping. The more precise and reliable method of functional mapping is represented by the intra-operative direct electrical stimulations (DES), which allow identification and preservation of essential pathways for motricity, sensibility and language, at each level of the central nervous system (cortico-subcortical). We report our experience of DES in the surgery of tumours and vascular malformations located in supra-tentorial brain eloquent areas, with a consecutive series of 60 patients operated on under general or local anaesthesia, from November 1996 until May 1999 in our department at La Salpêtrière Hospital. Presenting symptoms in the 60 subjects (39 males, 21 females, mean age: 45 years) were seizures in 37 cases with normal clinical examination, and mild neurological deficit in 29 cases. MRI showed 60 supra-tentorial brain lesions: 30 precentral, 12 postcentral, 14 perisylvian in the dominant hemisphere, 4 deep-seated. All subjects underwent surgical resection using DES, with supratentorial cortico-subcortical mapping under general anaesthesia for motor areas detection in 43 cases and under local anaesthesia for sensori-motor and/or language tasks in 17 cases. The final histological diagnosis was 44 gliomas (31 low-grade and 13 high-grade), 9 metastasis, 3 cavernomas, 4 arteriovenous malformations (AVM). Resection was total or subtotal in 52 cases (87%) and partial in 8 cases (13%). 29 patients had no post-operative deficit, while the other 31 patients were impaired post-operatively, with in all cases, except 3, a complete recovery delayed for 15 days to 3 months (overall morbidity: 5%). The median follow up was 14 months. Intra-operative direct electrical stimulations of the central nervous system constitute a reliable, precise and safe method, allowing the realization of a functional mapping useful for all operations of lesions located in eloquent areas. This technique allows a minimization of definitive post-operative neurological deficit, and concurrently an improvement in the quality of resection.

Three-dimensional Computed Tomographic Angiography in Detection of Cerebral Aneurysms in Acute Subarachnoid Hemorrhage

OBJECTIVE Three-dimensional computed tomographic angiography (CTA) is a recently developed imaging modality. We demonstrate the value of this noninvasive method in replacing digital subtraction angiography (DSA) in the detection of aneurysms of the circle of Willis in patients with subarachnoid hemorrhage admitted to our institution. METHODS A helical acquisition was performed for computed tomographic scans obtained for 120 patients with a 1 mm per second table speed and a 1-mm collimation, 1:1 pitch. Axial source images were transferred on a console Advantage Windows workstation (General Electric, Milwaukee, WI) and CTA was obtained using maximum intensity projection reconstruction. All patients had undergone DSA of the circle of Willis (80 patients preoperatively and 40 postoperatively). RESULTS A total of 129 aneurysms were detected in 107 patients. Three-dimensional CTA disclosed nothing abnormal in 13 patients. Ninety-two patients sustained one aneurysm, 10 patients sustained two, 3 patients sustained three, and 2 patients sustained four. All results were confirmed by DSA. In two cases, aneurysms of the middle cerebral artery were defected by CTA but not by DSA. When using angiographic views, the aneurysm was always masked by a branch of the middle cerebral artery. CONCLUSION The sensitivity of three-dimensional CTA is comparable with that of DSA, and its specificity is 100%. Because CTA is simple, quick, noninvasive, and reliable, we think that it can eventually replace DSA.

Oncological patterns of care and outcome for 952 patients with newly diagnosed glioblastoma in 2004

This report, an audit requested by the French government, describes oncological patterns of care, prognostic factors, and survival for patients with newly diagnosed and histologically confirmed glioblastoma multiforme (GBM) in France. The French Brain Tumor DataBase, which is a national multidisciplinary (neurosurgeons, neuropathologists, radiotherapists, neurooncologists, epidemiologists, and biostatisticians) network, prospectively collected initial data for the cases of GBM in 2004, and a specific data card was used to retrospectively collect data on the management and follow-up care of these patients between January 1, 2004, and December 1, 2006. We recorded 952 cases of GBM (male/female ratio 1.6, median age 63.9 years, mean preoperative Karnofsky performance status [KPS] 79). Surgery consisted of resection (RS; n = 541) and biopsy (n = 411); 180 patients did not have subsequent oncological treatment. After surgery, first-line treatment (n = 772) consisted of radiotherapy (RT) and temozolomide (TMZ) concomitant +/- adjuvant in 314 patients, RT alone in 236 patients, chemotherapy (CT) alone in 157 patients, and other treatment modalities in 65 patients. Median overall survival was 286 days (95% CI, 266-314) and was significantly affected by age, KPS, and tumor location. Median survival (days, 95% CI) associated with these main strategies, when analyzed by a surgical group, were as follows: RS + RT-TMZ((n=224)): 476 (441-506), biopsy + RT-TMZ((n=90)): 329 (301-413), RS + RT((n=147)): 363 (331-431), biopsy + RT((n=89)): 178 (153-237), RS + CT((n=61)): 245 (190-361), biopsy + CT((n=96)): 244 (198-280), and biopsy only((n=118)): 55 (46-71). This study illustrates the usefulness of a national brain tumor database. To our knowledge, this work is the largest report of recent GBM management in Europe.

A phase I study of an anti-epidermal growth factor receptor monoclonal antibody for the treatment of malignant gliomas.

OBJECTIVE Epidermal growth factor receptor (EGFR) is an operationally specific antigen in malignant gliomas; it is overexpressed in > 60% of these tumors, whereas its expression is very low in normal brain. This study aimed to evaluate whether an adequate amount of an anti-EGFR monoclonal antibody (MAb) could reach a tumor after a single intravenous administration. METHODS This study was open, nonrandomized, and uncontrolled. Single doses (20, 40, 100, 200, or 400 mg) of the murine MAb EMD55900 (MAb 425) were administered intravenously before surgery to 30 patients with malignant brain tumors. Serum samples were taken at defined time intervals during infusion, to determine EMD55900 concentrations, and 10, 21, and/or 42 days after infusion, to evaluate the development of human anti-mouse antibodies. Tumor samples were investigated for EGFR and EMD55900 contents. RESULTS Tolerance to EMD55900 was good. Increased liver transaminase levels were noted for three patients with Grade 1 toxicity. Twenty patients developed significant human anti-mouse antibody titers, without correlation with the administered dose. The median half-life of EMD55900 in serum ranged from 6 hours for 20 mg to 24 hours for 400 mg. In the membrane fractions of the tumors, EGFR saturation by EMD55900 varied with the injected dose of MAb. No binding was detected after a 20-mg dose. After doses of 40, 100, 200, and 400 mg, the mean saturation levels were 33, 73, 89, and 71%, respectively. CONCLUSION This study indicates that a single intravenous administration of EMD55900 is well tolerated and produces substantial in vivo tumor binding with doses > 100 mg.

Contrast enhancement in 1p/19q-codeleted anaplastic oligodendrogliomas is associated with 9p loss, genomic instability, and angiogenic gene expression

BACKGROUND The aim of this study was to correlate MRI features and molecular characteristics in anaplastic oligodendrogliomas (AOs). METHODS The MRI characteristics of 50 AO patients enrolled in the French national network for high-grade oligodendroglial tumors were analyzed. The genomic profiles and IDH mutational statuses were assessed using high-resolution single-nucleotide polymorphism arrays and direct sequencing, respectively. The gene expression profiles of 25 1p/19q-codeleted AOs were studied on Affymetrix expression arrays. RESULTS Most of the cases were frontal lobe contrast-enhanced tumors (52%), but the radiological presentations of these cases were heterogeneous, ranging from low-grade glioma-like aspects (26%) to glioblastoma-like aspects (22%). The 1p/19q codeletion (n = 39) was associated with locations in the frontal lobe (P = .001), with heterogeneous intratumoral signal intensities (P = .003) and with no or nonmeasurable contrast enhancements (P = .01). The IDH wild-type AOs (n = 7) more frequently displayed ringlike contrast enhancements (P = .03) and were more frequently located outside of the frontal lobe (P = .01). However, no specific imaging pattern could be identified for the 1p/19q-codeleted AO or the IDH-mutated AO. Within the 1p/19q-codeleted AO, the contrast enhancement was associated with larger tumor volumes (P = .001), chromosome 9p loss and CDKN2A loss (P = .006), genomic instability (P = .03), and angiogenesis-related gene expression (P < .001), particularly for vascular endothelial growth factor A and angiopoietin 2. CONCLUSION In AOs, the 1p/19q codeletion and the IDH mutation are associated with preferential (but not with specific) imaging characteristics. Within 1p/19q-codeleted AO, imaging heterogeneity is related to additional molecular alterations, especially chromosome 9p loss, which is associated with contrast enhancement and larger tumor volume.

Early radiologically proven rebleeding from intracranial cavernous angiomas: Report of 6 cases and review of the literature

SummaryAlthough intracranial cavernomas are known to cause haemorrhage, data concerning the frequency, severity and delay of recurrent bleedings are controversial. We report a series of 6 patients with histologically proven cavernoma, presenting with early clinical signs and radiological proof of rebleeding, that is occuring in the first month after initial overt haemorrhage. These 6 cases have been selected from a series of 142 patients seen between 1980 and 1995 in our department with cavernous angiomas or so-called AOVMs, of whom 93 presented with clinical symptoms of haemorrhage (34 patients presented symptoms of one or more rebleeding, but only 6 had radiological proof). All patients suffered neurological worsening due to the rebleeding, with an increase of the size of the haematoma on the CT scan. Five MRIs were performed at the acute stage: 3 showed evidence of cavernoma (60%). All patients underwent surgery at the acute stage of the rebleeding, with 5 improvements and 1 stabilization. A cavernous angioma was found in 5 cases at first surgery, but a further operation was necessary in the last patient to find and remove the cavernoma, after a second rebleeding following the first intervention.Our series reveals a high frequency of rebleeding after a first intracranial haemorrhage from a cavernous angioma, and highlights the precocity of such rebleedings. Therefore, we advocate early aggressive surgical management:in cases of cavernoma revealed by a first clinical overt haemorrhage, when there is strong radiological suspicion at the acute stage;and in all cases of rebleeding, even without radiological evidence of malformation, in the absence of vascular risk factors. Surgical indication must be discussed in particular cases of cavernomas of the brain stem when neither the haematoma nor the cavernoma reach the surface, and in deep supratentorial cavernomas, when the neurological status is good, because of the therapeutic risk.

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.

SNP Array Analysis Reveals Novel Genomic Abnormalities Including Copy Neutral Loss of Heterozygosity in Anaplastic Oligodendrogliomas

Anaplastic oligodendrogliomas (AOD) are rare glial tumors in adults with relative homogeneous clinical, radiological and histological features at the time of diagnosis but dramatically various clinical courses. Studies have identified several molecular abnormalities with clinical or biological relevance to AOD (e.g. t(1;19)(q10;p10), IDH1, IDH2, CIC and FUBP1 mutations). To better characterize the clinical and biological behavior of this tumor type, the creation of a national multicentric network, named “Prise en charge des OLigodendrogliomes Anaplasiques (POLA),” has been supported by the Institut National du Cancer (InCA). Newly diagnosed and centrally validated AOD patients and their related biological material (tumor and blood samples) were prospectively included in the POLA clinical database and tissue bank, respectively. At the molecular level, we have conducted a high-resolution single nucleotide polymorphism array analysis, which included 83 patients. Despite a careful central pathological review, AOD have been found to exhibit heterogeneous genomic features. A total of 82% of the tumors exhibited a 1p/19q-co-deletion, while 18% harbor a distinct chromosome pattern. Novel focal abnormalities, including homozygously deleted, amplified and disrupted regions, have been identified. Recurring copy neutral losses of heterozygosity (CNLOH) inducing the modulation of gene expression have also been discovered. CNLOH in the CDKN2A locus was associated with protein silencing in 1/3 of the cases. In addition, FUBP1 homozygous deletion was detected in one case suggesting a putative tumor suppressor role of FUBP1 in AOD. Our study showed that the genomic and pathological analyses of AOD are synergistic in detecting relevant clinical and biological subgroups of AOD.

Integrated multi-omics analysis of oligodendroglial tumours identifies three subgroups of 1p/19q co-deleted gliomas

Oligodendroglial tumours (OT) are a heterogeneous group of gliomas. Three molecular subgroups are currently distinguished on the basis of the IDH mutation and 1p/19q co-deletion. Here we present an integrated analysis of the transcriptome, genome and methylome of 156 OT. Not only does our multi-omics classification match the current classification but also reveals three subgroups within 1p/19q co-deleted tumours, associated with specific expression patterns of nervous system cell types: oligodendrocyte, oligodendrocyte precursor cell (OPC) and neuronal lineage. We confirm the validity of these three subgroups using public datasets. Importantly, the OPC-like group is associated with more aggressive clinical and molecular patterns, including MYC activation. We show that the MYC activation occurs through various alterations, including MYC genomic gain, MAX genomic loss, MYC hypomethylation and microRNA-34b/c down-regulation. In the lower grade glioma TCGA dataset, the OPC-like group is associated with a poorer outcome independently of histological grade. Our study reveals previously unrecognized heterogeneity among 1p/19q co-deleted tumours.

Intra arterial chemotherapy with ACNU and radiotherapy in inoperable malignant gliomas

SummaryFor the non-operable malignant glioma patients, prognosis remains poor, with a survival of 8 months for the glioblastomas (G), and 15 months for anaplastic astrocytomas (AA). 27 histologic proven malignant gliomas (17 AA and 10 G) were treated between April 1991 and June 1992. Median age was 48 years. The therapeutic protocol consisted of three courses of intra arterial chemotherapy (IAC) with ACNU, at intervals of six weeks, and a localised 60 Gy radiotherapy between the first and the second IAC course. 72 courses of IAC were delivered (2,4 per patient). Response rate was 51,8%. Median survival (MS) was 13 months, with a survival rate of 28% at 24 months. For the AA, MS was 21 months, with a survival rate of 37% at 24 months. For the G, median survival was 10 months. Responders were 65 % for AA, 30% for G. Non responders all died before 24 months had relapsed with a MS of 9 months. 54% of responding patients had a 2 years survival. Toxicity were acceptable with 7% of haematological toxicity and a partial loss of visual acuity in 11% of the cases. No chronic neurological sequellae were noted. We compare theses results with two previous trials, concerning inoperable patients, treated by an association of radiotherapy and systemic chemotherapy. Survival seems to be equivalent with HeCNU and with this treatment, but toxicity decreases with ACNU. Early radiotherapy does not increase complications. This treatment can be used for patients with inoperable malignant gliomas.