[Show abstract][Hide abstract] ABSTRACT: Glioblastomas (GBM) are some bad prognosis brain tumors despite a conventional treatment associating surgical resection and subsequent radio-chemotherapy. Among these heterogeneous tumors, a subpopulation of chemo- and radioresistant GBM stem-like cells appears to be involved in the systematic GBM recurrence. Moreover, recent studies showed that differentiated tumor cells may have the ability to dedifferentiate and acquire a stem-like phenotype, a phenomenon also called plasticity, in response to microenvironment stresses such as hypoxia. We hypothesized that GBM cells could be subjected to a similar dedifferentiation process after ionizing radiations (IRs), then supporting the GBM rapid recurrence after radiotherapy. In the present study we demonstrated that subtoxic IR exposure of differentiated GBM cells isolated from patient resections potentiated the long-term reacquisition of stem-associated properties such as the ability to generate primary and secondary neurospheres, the expression of stemness markers and an increased tumorigenicity. We also identified during this process an upregulation of the anti-apoptotic protein survivin and we showed that its specific downregulation led to the blockade of the IR-induced plasticity. Altogether, these results demonstrated that irradiation could regulate GBM cell dedifferentiation via a survivin-dependent pathway. Targeting the mechanisms associated with IR-induced plasticity will likely contribute to the development of some innovating pharmacological strategies for an improved radiosensitization of these aggressive brain cancers.
Cell Death & Disease 11/2014; 5:e1543. · 5.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gli astrocitomi anaplastici e i glioblastomi rappresentano i tumori maligni primitivi più frequenti e più aggressivi del sistema nervoso centrale. Essi colpiscono dei pazienti giovani e la loro prognosi, anche se notevolmente migliorata negli ultimi anni, resta drammatica. Il loro trattamento costituisce una sfida fondamentale per la neuro-oncologia. Sul piano della diagnostica per immagini, la risonanza magnetica (RM) morfologica resta lo standard attuale per la diagnosi e il follow-up di questi tumori. Tuttavia, numerosissimi studi insistono sull’apporto della diagnostica per immagini multimodale (sequenza di perfusione, di diffusione in RM e spettroscopia RM in particolare) per migliorare il nostro approccio diagnostico e la valutazione terapeutica. D’altronde, importanti progressi sono stati realizzati negli ultimi anni in biologia molecolare, permettendo di affinare la diagnosi e di individuare degli indicatori prognostici. Anche sul piano terapeutico, sono stati osservati importanti progressi, sia a livello delle tecniche chirurgiche che a livello di quelle mediche, che permettono di migliorare la mediana di sopravvivenza, la qualità della vita e le capacità funzionali di questi pazienti. Il trattamento postoperatorio di prima linea si basa sull’associazione chemioterapia-radioterapia nella maggioranza dei casi. Il trattamento di seconda linea è meno ben codificato: tuttavia, numerosi studi hanno dimostrato l’apporto del bevacizumab in questa indicazione. Peraltro, nuove molecole e/o strategie terapeutiche sono attualmente in corso di valutazione, permettendo di sperare in un miglioramento della prognosi e della qualità della vita in futuro.
[Show abstract][Hide abstract] ABSTRACT: Purpose
Because lactate accumulation is considered a surrogate for hypoxia and tumor radiation resistance, we studied the spatial distribution of the lactate-to-N-acetyl-aspartate ratio (LNR) before radiation therapy (RT) with 3D proton magnetic resonance spectroscopic imaging (3D-1H-MRSI) and assessed its impact on local tumor control in glioblastoma (GBM).
Methods and Materials
Fourteen patients with newly diagnosed GBM included in a phase 2 chemoradiation therapy trial constituted our database. Magnetic resonance imaging (MRI) and MRSI data before RT were evaluated and correlated to MRI data at relapse. The optimal threshold for tumor-associated LNR was determined with receiver-operating-characteristic (ROC) curve analysis of the pre-RT LNR values and MRI characteristics of the tumor. This threshold was used to segment pre-RT normalized LNR maps. Two spatial analyses were performed: (1) a pre-RT volumetric comparison of abnormal LNR areas with regions of MRI-defined lesions and a choline (Cho)-to- N-acetyl-aspartate (NAA) ratio ≥2 (CNR2); and (2) a voxel-by-voxel spatial analysis of 4,186,185 voxels with the intention of evaluating whether pre-RT abnormal LNR areas were predictive of the site of local recurrence.
A LNR of ≥0.4 (LNR-0.4) discriminated between tumor-associated and normal LNR values with 88.8% sensitivity and 97.6% specificity. LNR-0.4 voxels were spatially different from those of MRI-defined lesions, representing 44% of contrast enhancement, 64% of central necrosis, and 26% of fluid-attenuated inversion recovery (FLAIR) abnormality volumes before RT. They extended beyond the overlap with CNR2 for most patients (median: 20 cm3; range: 6-49 cm3). LNR-0.4 voxels were significantly predictive of local recurrence, regarded as contrast enhancement at relapse: 71% of voxels with a LNR-0.4 before RT were contrast enhanced at relapse versus 10% of voxels with a normal LNR (P<.01).
Pre-RT LNR-0.4 in GBM indicates tumor areas that are likely to relapse. Further investigations are needed to confirm lactate imaging as a tool to define additional biological target volumes for dose painting.
International journal of radiation oncology, biology, physics 01/2014; · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
Central neurocytoma (CN) is a rare intraventricular tumour. Surgery has been highly recommended for CN, although it entails a significant chance to harm the patient. We aimed to provide new data that would support surgical decision-making and optimise patient information about outcomes after surgery.
Under the auspices of the French Society of Neurosurgery, we conducted a multi-institutional database search in 23 academic hospitals. In all, we reviewed the relevant clinical and radiological data of 82 patients who were operated on for CN between 1984 and 2008, and had their diagnosis confirmed by central pathological review.
The median follow-up was 61 months (range, 6–96 months). Gross total resection (GTR) was achieved in 48 % of the patients, and subtotal resection (STR) in 52 %. The 5-year overall survival rate was 93.8 % (95 % CI, 93.7–93.9). The 5-year progression-free survival rate was 92.1 % (95 % CI, 91.90–92.2) in patients who underwent GTR, compared with 55.3 % (95 % CI, 55.1–55.5) in patients who had STR (p = 0.01). The overall perioperative complication rate was 66 %. The main causes of postoperative disability were some degree of postoperative paresis and/or aphasia (39 %), memory difficulties (29 %) and temporary hydrocephalus (26 %). GTR was not associated with an increased rate of postoperative complications compared with STR. At last follow-up, Karnofsky Performance Score was at least equal to 80 for 90.6 % of the tested patients.
Our series emphasised that maximal surgical resection of CNs offers favourable benefit-risk ratio. These data are of importance to properly counsel patients regarding expected outcomes, and to plan relevant preoperative and postoperative investigations like language and memory function evaluation.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Based on our previous results showing the involvement of the farnesylated form of RhoB in glioblastoma radioresistance, we designed a phase II trial associating the farnesyltransferase inhibitor Tipifarnib with radiotherapy in patients with glioblastoma and studied the prognostic values of the proteins which we have previously shown control this pathway. PATIENTS AND METHODS: Patients were treated with 200mg Tipifarnib (recommended dose (RD)) given continuously during radiotherapy. Twenty-seven patients were included in the phase II whose primary end-point was time to progression (TTP). Overall survival (OS) and biomarker analysis were secondary end-points. Expressions of αvβ3, αvβ5 integrins, FAK, ILK, fibroblast growth factor 2 (FGF2) and fibroblast growth factor receptor 1 (FGFR1) were studied by immuno-histochemistry in the tumour of the nine patients treated at the RD during the previously performed phase I and on those of the phase II patients. We evaluated the correlation of the expressions of these proteins with the clinical outcome. RESULTS: For the phase II patients median TTP was 23.1weeks (95%CI=[15.4; 28.2]) while the median OS was 80.3weeks (95%CI=[57.8; 102.7]). In the pooled phase I and II population, median OS was 60.4w (95%CI=[47.3; 97.6]) while median TTP was 18.1w (95%CI=[16.9; 25.6]). FGFR1 over-expression (HR=4.65; 95%CI=[1.02; 21.21], p=0.047) was correlated with shorter TTP while FGFR1 (HR=4.1 (95% CI=[1.09-15.4]; p=0.036)) and αvβ3 (HR=10.38 (95%CI=[2.70; 39.87], p=0.001)) over-expressions were associated with reduced OS. CONCLUSION: Association of 200mg Tipifarnib with radiotherapy shows promising OS but no increase in TTP compared to historical data. FGFR1 and αvβ3 integrin are independent bad prognostic factors of OS and TTP.
European journal of cancer (Oxford, England: 1990) 04/2013; · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: To integrate 3D MR spectroscopy imaging (MRSI) in the treatment planning system (TPS) for glioblastoma dose painting to guide simultaneous integrated boost (SIB) in intensity-modulated radiation therapy (IMRT). METHODS: For sixteen glioblastoma patients, we have simulated three types of dosimetry plans, one conventional plan of 60-Gy in 3D conformational radiotherapy (3D-CRT), one 60-Gy plan in IMRT and one 72-Gy plan in SIB-IMRT. All sixteen MRSI metabolic maps were integrated into TPS, using normalization with color-space conversion and threshold-based segmentation. The fusion between the metabolic maps and the planning CT scans were assessed. Dosimetry comparisons were performed between the different plans of 60-Gy 3D-CRT, 60-Gy IMRT and 72-Gy SIB-IMRT, the last plan was targeted on MRSI abnormalities and contrast enhancement (CE). RESULTS: Fusion assessment was performed for 160 transformations. It resulted in maximum differences <1.00 mm for translation parameters and <=1.15[degree sign] for rotation. Dosimetry plans of 72-Gy SIB-IMRT and 60-Gy IMRT showed a significantly decreased maximum dose to the brainstem (44.00 and 44.30 vs. 57.01 Gy) and decreased high dose-volumes to normal brain (19 and 20 vs. 23% and 7 and 7 vs. 12%) compared to 60-Gy 3D-CRT (p < 0.05). CONCLUSIONS: Delivering standard doses to conventional target and higher doses to new target volumes characterized by MRSI and CE is now possible and does not increase dose to organs at risk. MRSI and CE abnormalities are now integrated for glioblastoma SIB-IMRT, concomitant with temozolomide, in an ongoing multi-institutional phase-III clinical trial. Our method of MR spectroscopy maps integration to TPS is robust and reliable; integration to neuronavigation systems with this method could also improve glioblastoma resection or guide biopsies.
[Show abstract][Hide abstract] ABSTRACT: In this paper, we report a case study of a 31-year-old multilingual female (LK) who presented with a left prefrontal brain tumour (WHO grade II glioma). LK is a late trilingual person whose first language is German. She had been learning English and French for 10 years when she moved to France at the age of 20 and now mostly uses French. German (L1) and French (L3) were assessed using a selection of sub-tests taken from the MT 86, the French version of the BDAE, the ECOSSE, the MEC, the German BAT, and, a non-standardized German adaptation of parts of the MEC. Preoperatively, LK had no language deficit. She was operated on under awake craniotomy, and both languages were mapped. Direct intraoperative electrical stimulation mapping showed that i) L1 and L3 were represented by both distinct and overlapping areas within the left (dominant) inferior frontal cortex, but shared the same subcortical tracts, and ii) the left dorsolateral prefrontal cortex was engaged when switching from one language to another. Since surgery, the patient has been followed longitudinally, with six-monthly assessments of her language skills using the same test battery. Her L1 and L3 language skills have been intact for 24 months postoperatively. After presenting the behavioural and brain mapping data, we discuss their relevance with respect to the organization of language skills within the frontal cortex and deep frontal structures.
Journal of Neurolinguistics 11/2012; 25:567-578. · 1.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and purposeSeizures can occur in patients who have surgery for a chronic subdural hematoma. However, the incidence of seizures and their impact on the clinical course of patients in the perioperative period is not well known.Methods
In this retrospective study, we reviewed 161 cases of patients treated for chronic subdural hematoma in our institution. The surgical procedures consisted in trephine craniotomy in 156 cases, burr-hole craniotomy in three cases, and bone flap craniotomy in two cases. All the patients had systematic antiepileptic drug prophylaxis.ResultsIn our patients’ population, the incidence of seizures was 10.6% before surgery and 14.9% after surgery. Low initial score on the Glasgow Coma Scale (P < 0.001) and preoperative cognitive impairment (P = 0.005) were associated with a higher rate of postoperative seizures. In our study, the mortality rate was 14.9%. Low initial score on the Glasgow Coma Scale (P = 0.068) and postoperative seizures (P = 0.002) were associated with a higher mortality rate.ConclusionsWe have shown that patients suffering from seizures may have worse outcome. The benefit of a systematic perioperative prophylaxis using antiepileptic drugs has to be evaluated.RésuméDescription et objectifs de l’étudeBien que l’épilepsie soit une complication classique chez les patients opérés d’hématome sous-dural, l’incidence des crises postopératoires (1–23,4 %) est très variable dans la littérature. Notre étude a pour objectif d’apprécier l’incidence des crises d’épilepsie postopératoires, de rechercher d’éventuels facteurs favorisant leur survenue et d’évaluer leur impact sur la mortalité.MéthodeNous avons mené une étude rétrospective sur 161 patients opérés d’un hématome sous-dural chronique dans notre centre. Tous les malades ont été traités par tréphine, à l’exception de cinq patients traités par un trou de trépan ou un volet (respectivement trois et deux patients). Tous ont reçu une prophylaxie antiépileptique périopératoire.RésultatsDans cette étude, l’incidence des crises était de 10,6 % en préopératoire et de 14,9 % en postopératoire. La présence de troubles de la vigilance et/ou de troubles cognitifs à l’admission était associée à un taux plus élevé de crises postopératoires (p < 0,05). Les crises postopératoires étaient associées à une mortalité plus élevée (p < 0,002).Conclusion
Notre étude montre que les crises ont très vraisemblablement un impact défavorable sur le devenir des patients. Il nous apparaît nécessaire de réaliser une étude prospective randomisée visant à établir le bénéfice potentiel d’une prophylaxie antiépileptique périopératoire standardisée chez les patients opérés d’hématome sous-dural chronique.
[Show abstract][Hide abstract] ABSTRACT: Seizures can occur in patients who have surgery for a chronic subdural hematoma. However, the incidence of seizures and their impact on the clinical course of patients in the perioperative period is not well known.
In this retrospective study, we reviewed 161 cases of patients treated for chronic subdural hematoma in our institution. The surgical procedures consisted in trephine craniotomy in 156 cases, burr-hole craniotomy in three cases, and bone flap craniotomy in two cases. All the patients had systematic antiepileptic drug prophylaxis.
In our patients' population, the incidence of seizures was 10.6% before surgery and 14.9% after surgery. Low initial score on the Glasgow Coma Scale (P<0.001) and preoperative cognitive impairment (P=0.005) were associated with a higher rate of postoperative seizures. In our study, the mortality rate was 14.9%. Low initial score on the Glasgow Coma Scale (P=0.068) and postoperative seizures (P=0.002) were associated with a higher mortality rate.
We have shown that patients suffering from seizures may have worse outcome. The benefit of a systematic perioperative prophylaxis using antiepileptic drugs has to be evaluated.
[Show abstract][Hide abstract] ABSTRACT: Among the potential approaches to access the petroclival area, epidural anterior petrosectomy (EAP) appears to be the most direct and conservative transpetrous route. In this article, we aim to detail the relevant surgical steps necessary to perform EAP in a reproducible and safe manner.
The temporo-pterional bone flap is tailored to access the floor of the middle fossa and expose the foramen ovale and foramen spinosum. Elevation of the dura covering the upper surface of the petrous apex is conducted medially toward the level of the petrous ridge. Identification of the landmarks of the rhomboid fossa delineates the limits of the drilling zone (necessary for removal of the petrous apex)-beneath Meckel's cave and just anterior to the anterior margin of the internal auditory meatus. The tentorium is divided at its free edge and is followed by opening of the posterior fossa dura.
Epidural anterior petrosectomy is a conservative trans-petrous approach that offers an excellent direct surgical corridor for exposure of disease processes involving Meckel's cave, the petroclival area and the ventrolateral pons.
[Show abstract][Hide abstract] ABSTRACT: The authors undertook this study to examine the surgical approaches used to treat posterior petrous bone meningiomas at a single institution and retrospectively evaluate their surgical strategy based on a previously published classification.
Cases in which craniotomies were performed to treat posterior petrous bone meningiomas between 2002 and 2010 were retrospectively reviewed. Data were examined from 57 patients who were treated for 59 tumors. The tumors were classified into 3 types according to the location of their primary dural attachment: Type A, located around the porus trigeminus (33 tumors); Type M, located at the level of the porus of the internal auditory canal (IAC) (12 tumors); and Type P, located laterally to the IAC (14 tumors). The median tumor diameter was 34 mm (range 20-67 mm).
The choice of the approach was based on tumor location, as the displacement of vascular structures and cranial nerves was primarily determined by the site of dural attachment on the posterior petrous bone. An anterior petrosectomy was performed in 82% of Type A meningiomas, and a retrosigmoid approach was used in 86% of Type P meningiomas. The spectrum of approaches was less uniform for Type M meningiomas. Overall, total resection was obtained in 39% of all cases, and in 18%, 50%, and 86% of Type A, Type M, and Type P tumors, respectively. The postoperative mortality rate was 8.8% (5 deaths among 57 patients), and all 5 patients who died during the early postoperative period had large Type A tumors. At last follow-up, the functional preservation of the facial nerve was excellent in 49 (94%) of the 52 surviving patients.
The authors believe that proper selection of the approach favorably impacts functional outcome in patients undergoing surgery for the treatment of skull base tumors. In the authors' case series of posterior petrous bone meningiomas, Type P and most Type M tumors were safely managed through a regular retrosigmoid approach, whereas Type A tumors were optimally treated via an epidural anterior petrosectomy.
[Show abstract][Hide abstract] ABSTRACT: Surgical resection of mass lesions in Broca's area is controversial. To demonstrate that pathology may influence the localization of functional areas and language performance, we reviewed our experience of awake craniotomies in Broca's area.
Sixteen consecutive patients who underwent awake craniotomy and direct brain mapping for resective surgery in Broca's area were analyzed. Six patients had well-circumscribed lesions, whereas 10 patients had infiltrative gliomas. A short version of the Boston Diagnostic Aphasia Examination test was used for language assessment.
Inferior frontal language sites were found in all but 4 patients. In patients with cavernomas or well-circumscribed tumors, 9 of 9 (100%) of the positive sites were located in the classic Broca's area (BA 44/45). By contrast, in those patients with gliomas, only 5 of 20 (25%) of the positive sites were located in BA 44/45. Patients with infiltrative gliomas demonstrated more deficits in the pre and postoperative periods than those with well-circumscribed mass lesions. All patients returned to their baseline abilities within 6 months.
Intraoperative language maps generated in cases with well-circumscribed lesions are different from those generated in cases with infiltrative gliomas. This supports the view that interindividual language variability and displacement of critical structures by mass effect should first be considered for circumscribed lesions, whereas reshaping should largely be attributed to brain plasticity in gliomas. Surgery in Broca's area can be safely conducted using awake craniotomy and brain mapping.
[Show abstract][Hide abstract] ABSTRACT: To assess the feasibility of synthesis of O-(2-[(18)F]-fluoroethyl)-l-tyrosine (FET), a new positron emission tomographic (PET) tracer described in several studies but not yet considered standard in management of glioma, in routine practice and to determine FET uptake in a homogeneous group of patients with suspected high-grade glioma.
Prospective nonrandomized trial.
Twelve patients with suspicion of high-grade glioma.
The mean (SD) FET uptake ratio was 3.15 (0.72) for the 12 patients and 3.16 (0.75) for the 11 patients with glioblastoma.
The initial results are promising and indicate that FET PET is a valuable and applicable tool for the imaging of high-grade glioma.
Archives of neurology 03/2010; 67(3):370-2. · 7.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is increasing evidence that the extent of tumor removal in low-grade glioma surgery is related to patient survival time. Thus, the goal of resecting the largest amount of tumor possible without leading to permanent neurological sequelae is a challenge for the neurosurgeon. Electrical stimulation of the brain to detect cortical and axonal areas involved in motor, language, and cognitive function and located within the tumor or along its boundaries has become an essential tool in combination with awake craniotomy. Based on a literature review, discussions within the European Low-Grade Glioma Group, and illustrative clinical experience, the authors of this paper provide an overview for neurosurgeons, neurophysiologists, linguists, and anesthesiologists as well as those new to the field about the stimulation techniques currently being used for mapping sensorimotor, language, and cognitive function in awake surgery for low-grade glioma. The paper is intended to help the understanding of these techniques and facilitate a comparison of results between users.